Chemistry:Monoamine releasing agent

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Short description: Class of compounds
"Releasing agent" redirects here. For mold release agents, see Release agent.

File:Amphetamine structure.svg
Amphetamine, the prototypical monoamine releasing agent, which induces the release of dopamine and norepinephrine.[1]

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitters and hence enhanced signaling by those neurotransmitters.[2][3][4][1][5] The monoamine neurotransmitters include serotonin, norepinephrine, and dopamine; MRAs can induce the release of one or more of these neurotransmitters.[2][3][4][1][5]

MRAs work by reversing the direction of the monoamine transporters (MATs), including the serotonin transporter (SERT), norepinephrine transporter (NET), and/or dopamine transporter (DAT), causing them to promote efflux of non-vesicular cytoplasmic monoamine neurotransmitter rather than reuptake of synaptic monoamine neurotransmitter.[5][6][1][7] Many, but not all MRAs, also reverse the direction of the vesicular monoamine transporter 2 (VMAT2), thereby additionally resulting in efflux of vesicular monoamine neurotransmitter into the cytoplasm.[5]

A variety of different classes of drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters.[2][3] These include psychostimulants and appetite suppressants acting as dopamine and norepinephrine releasers like amphetamine, methamphetamine, and phentermine; sympathomimetic agents acting as norepinephrine releasers like ephedrine and pseudoephedrine; non-stimulant appetite suppressants acting as serotonin releasers like fenfluramine and chlorphentermine; and entactogens acting as releasers of serotonin and/or other monoamines like MDMA.[2][3] Trace amines like phenethylamine and tryptamine, as well as the monoamine neurotransmitters themselves, are endogenous MRAs.[2][3][4] It is thought that monoamine release by endogenous mediators may play some physiological regulatory role.[4]

MRAs must be distinguished from monoamine reuptake inhibitors (MRIs) and monoaminergic activity enhancers (MAEs), which similarly increase synaptic monoamine neurotransmitter levels and enhance monoaminergic signaling but work via distinct mechanisms.[5][1][8][9]

Types and selectivity

MRAs can be classified by the monoamines they mainly release, although these drugs lie on a spectrum:[2][3][4][5]

The differences in selectivity of MRAs is the result of different affinities as substrates for the monoamine transporters, and thus differing ability to gain access into monoaminergic neurons and induce monoamine neurotransmitter release.

As of present, no selective DRAs are known. This is because it has proven extremely difficult to separate DAT affinity from NET affinity and retain releasing efficacy at the same time.[10] Several selective SDRAs, including tryptamine, (+)-α-ethyltryptamine (αET), 5-chloro-αMT, and 5-fluoro-αET, are known.[11][12] However, besides their serotonin release, many of these compounds additionally act as non-selective serotonin receptor agonists, including of the serotonin 5-HT2A receptor (with accompanying hallucinogenic effects), and some of them are known to act as monoamine oxidase inhibitors.[11][12]

Effects and uses

MRAs can produce varying effects depending on their selectivity for inducing the release of different monoamine neurotransmitters.[3]

Selective SRAs such as chlorphentermine have been described as dysphoric and lethargic.[13][14] Less selective SRAs that also stimulate the release of dopamine, such as methylenedioxymethamphetamine (MDMA), are described as more pleasant, more reliably elevating mood and increasing energy and sociability.[15] SRAs have been used as appetite suppressants and as entactogens. They have also been proposed for use as more effective antidepressants and anxiolytics than selective serotonin reuptake inhibitors (SSRIs) because they can produce much larger increases in serotonin levels in comparison.[16]

DRAs, usually non-selective for both norepinephrine and dopamine, have psychostimulant effects, causing an increase in energy, motivation, elevated mood, and euphoria.[17] Other variables can significantly affect the subjective effects, such as infusion rate (increasing positive effects of DRAs) and psychological expectancy effects.[18] They are used in the treatment of attention deficit hyperactivity disorder (ADHD), as appetite suppressants, wakefulness-promoting agents, to improve motivation, and are drugs of recreational use and misuse.

Selective NRAs are minimally psychoactive, but as demonstrated by ephedrine, may be distinguished from placebo, and may trends towards liking.[19] They may also be performance-enhancing,[20] in contrast to reboxetine which is solely a norepinephrine reuptake inhibitor.[21][22] In addition to their central effects, NRAs produce peripheral sympathomimetic effects like increased heart rate, blood pressure, and force of heart contractions. They are used as nasal decongestants and bronchodilators, but have also seen use as wakefulness-promoting agents, appetite suppressants, and antihypotensive agents. They have additionally seen use as performance-enhancing drugs, for instance in sports.

Mechanism of action

Mechanisms of monoamine release by MRAs

MRAs induce the release of the monoamine neurotransmitters serotonin, norepinephrine, and/or dopamine from monoaminergic neurons in the brain and/or periphery.[3][23][24] MRAs are substrates of the plasma membrane-associated monoamine transporters (MATs), including of the serotonin transporter (SERT), norepinephrine transporter (NET), and/or dopamine transporter (DAT), and enter presynaptic monoaminergic neurons via these transporters.[23][3][24][25] To a much lesser extent, sufficiently lipophilic MRAs may also passively diffuse into monoaminergic neurons.[23][24] Once in the intracellular space of the neuron, MRAs reverse the direction of the MATs, as well as of the organic cation transporter 3 (OCT3),[23][26] such that they mediate efflux of cytosolic monoamine neurotransmitters into the extracellular synaptic cleft rather than the usual reuptake.[23][24] Many, though notably not all MRAs,[5][27][note 1] additionally act at the vesicular monoamine transporter 2 (VMAT2) on synaptic vesicles to enhance the pool of cytosolic monoamine neurotransmitters available for efflux.[23][5][31][24] However, MRAs can still induce monoamine release without VMAT2, for instance by releasing newly synthesized cytosolic neurotransmitters.[23][32][33] In addition to their induction of monoamine release, MRAs act less potently as monoamine reuptake inhibitors (MRIs).[23][24][2][1] This is due to substrate competition with monoamine neurotransmitters for the MATs[25][6][1] and/or induction of MAT internalization and consequent inactivation.[23][34] The monoamine neurotransmitters released by MRAs bind to and activate monoamine receptors on presynaptic and postsynaptic neurons to facilitate monoaminergic neurotransmission.[25][35] As such, MRAs can be described as indirect monoamine receptor agonists.[35][1]

The mechanisms by which MRAs induce MAT reverse transport and efflux are complex and incompletely understood.[23][24][36][37] The process appears to depend on a number of intracellular changes, including sodium ion (Na+) and calcium ion (Ca2+) elevation, protein kinase C (PKC) activation, and Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) activation, among others.[24][23][36][37][38] Activation of protein kinases including PKC, CaMKIIα, and others results in phosphorylation of the MATs causing them to mediate efflux instead of reuptake.[23][36][39][34] Exactly how MRAs induce the preceding effects is unclear however.[23][24][36][34][37] A more recent study suggests that intracellular Ca2+ elevation, PKC activation, and CaMKIIα might all be dispensable for MRA-induced monoamine release, but more research is needed.[40]

The trace amine-associated receptor 1 (TAAR1) is a receptor for trace amines like β-phenethylamine and tryptamine, as well as for monoamine neurotransmitters like dopamine and serotonin, and is a known target of many MRAs, such as amphetamine and methamphetamine.[41] The TAAR1 is a largely intracellular receptor expressed both in presynaptic and postsynaptic monoaminergic neurons and appears to be extensively co-localized with MATs in the brain.[42][41] Some in-vitro studies have found that TAAR1 agonism by MAT substrates like MRAs can produce PKC activation and thereby induce MAT reverse transport and monoamine efflux.[42][43] As such, TAAR1 agonism, coupled with MAT substrate activity, could mediate or contribute to the monoamine release of MRAs.[42][43] However, findings in this area are conflicting, with other studies unable to replicate the results.[44][45][46][47][48][49] In addition, MRAs can still induce monoamine efflux in the absence of TAAR1 in vitro,[50][51][42] well-known MRAs like amphetamine and methamphetamine exhibit only low-potency human TAAR1 agonism[52][53][35] that is of uncertain general significance in humans,[26][54][55][56][57] many other MRAs are inactive as TAAR1 agonists in humans,[52][53][25][26][note 2] the monoamine release and behavioral effects of amphetamines are not only preserved but substantially augmented in TAAR1 knockout mice,[44][42] and the monoamine release and behavioral effects of amphetamines are strongly reduced or abolished in mice with TAAR1 overexpression.[44][59] Besides induction of monoamine release, TAAR1 agonism, as well as other mechanisms, may mediate MAT internalization.[23][60] MAT internalization may limit the capacity of MRAs to induce MAT reverse transport and monoamine efflux.[61][62] TAAR1 signaling also activates G protein-coupled inwardly rectifying potassium channels (GIRKs) and thereby robustly inhibits the firing rates of brain monoaminergic neurons and suppresses exocytotic monoamine release.[63][42][46] Due to the preceding mechanisms, potent TAAR1 agonism by MRAs that possess this action may actually auto-inhibit and constrain their monoaminergic effects.[56][26][64][49]

Although induction of MAT reverse transport and consequent monoamine efflux is the leading theory of how MRAs act, an alternative and more recent theory has proposed that amphetamine, at therapeutic doses, may not actually act by inducing DAT reverse transport and dopamine efflux, but instead by augmenting exocytotic dopamine release and hence by enhancing phasic rather than tonic dopaminergic signaling.[23][65][66] According to this model, DAT reverse transport may only be relevant at supratherapeutic doses and may be more associated with toxicity, for instance induction of psychosis.[23][65][66] It is unclear how amphetamine might act to enhance exocytotic dopamine release, and more research is needed to evaluate this theory.[23][65][66]

Aside from the mechanisms mediating the monoamine release of MRAs, other targets of some MRAs, such as the intracellular sigma σ1 receptor, have been found to inhibit MRA-induced monoamine efflux via interactions with the MATs.[67][68] Conversely, activation of the sigma σ2 receptor has been found to potentiate amphetamine-induced dopamine efflux.[69] The mechanism mediating this effect is unknown, but it has been postulated that it may be due to elevation of intracellular calcium and consequent downstream effects.[69]

Differences from physiological release and reuptake inhibitors

The neurotransmitter release induced by MRAs is very different from normal exocytotic monoamine release, in which action potentials trigger synaptic vesicles to fuse with the cell membrane and release neurotransmitters into the synaptic cleft.[23][3] In relation to this, MRAs promote tonic monoaminergic signaling, whereas normal exocytotic monoamine release involves phasic monoaminergic signaling.[23]

The enhancement of monoaminergic signaling by MRAs also differs from that with MRIs.[3][5][23][36] Because MRIs block monoamine neurotransmitter reuptake and consequent inactivation following action potentials and exocytotic release, they preferentially augment phasic monoaminergic signaling rather than tonic signaling.[3] In addition, inhibitory presynaptic and somatodendritic monoamine autoreceptors, including serotonin 5-HT1A and 5-HT1B autoreceptors, dopamine D2 and D3 autoreceptors, and α2-adrenergic autoreceptors, respond to elevated synaptic monoamine neurotransmitter levels by inhibiting presynaptic monoaminergic neuron firing rates, and this substantially limits the effects of MRIs.[3][5][35] In contrast, MRAs do not depend on action potentials to induce monoamine release, and thus are able to largely bypass the negative feedback mediated by autoreceptors.[3] Relatedly, MRAs can induce far greater maximal increases in monoamine neurotransmitter levels than MRIs.[3] For instance, MRIs can achieve maximal elevations in brain monoamine levels of about 5- to 10-fold in animals, whereas MRAs can produce elevations of as much as 10- to 50-fold, with no clear ceiling limit.[1][70][71][72][73][3][74] Since MRAs depend on uptake by the MATs to induce monoamine release, their mediation of monoamine release and consequent effects can be blocked by MRIs.[3][23][24][75]

Structural requirements and partial MRAs

Generic pharmacophore for MRAs.[5] Substitutions at the nitrogen, α-carbon, or phenyl ring extending beyond the red circle will result in partial releasers, transporter blockers, or be inactive.[5]

There is a constrained and relatively small molecular size requirement for compounds to act as MRAs.[5] This is because they must be small enough to serve as substrates of the monoamine transporters and thereby be transported inside of monoaminergic neurons by these proteins, in turn allowing them to induce monoamine neurotransmitter release.[5][23] Compounds with chemical features extending beyond the size constraints for releasers will instead act as partial releasers, reuptake inhibitors, or be inactive.[5][23] Partial releasers show reduced maximal efficacy in releasing monoamine neurotransmitters compared to conventional full releasers.[5][6][23] While most MRAs are full releasers, a number of partial releasers are known and may have atypical properties.[5][6] Examples of partial releasers include 3,4-methylenedioxyethylamphetamine (MDEA), N-ethylnaphthylaminopropane (ENAP), 3-trifluoromethyl-4-chlorophenylpiperazine (TFMCPP), para-nitrophenylpiperazine (pNPP), bretisilocin, and psilocin.[5][6][76][77][78] The mechanisms responsible for the differences between full releasers and partial releasers are largely unknown.[6]

DAT "inverse agonists"

Dopamine reuptake inhibitors (DRIs) have been grouped into two types, typical or conventional DRIs like cocaine, WIN-35428 (β-CFT), and methylphenidate that produce potent psychostimulant, euphoric, and reinforcing effects, and atypical DRIs like vanoxerine (GBR-12909), modafinil, benztropine, and bupropion, which do not produce such effects or have greatly reduced such effects.[7][6][5][79] It has been proposed that typical DRIs may not actually be acting primarily as DRIs but rather as dopamine releasing agents (DRAs) via mechanisms distinct from conventional substrate-type DRAs like amphetamines.[7] A variety of different pieces of evidence support this hypothesis and help to explain otherwise confusing findings.[7] For example, typical DRIs like cocaine and methylphenidate can robustly increase brain dopamine levels similarly to substrate-type DRAs like amphetamine, whereas atypical DRIs, which are viewed as simple competitive reuptake inhibitors, achieve much more modest increases.[7][80][81][82] Under this model, typical cocaine-like DRIs have been referred to with the new label of dopamine transporter (DAT) "inverse agonists" to distinguish them from conventional substrate-type DRAs.[7] An alternative theory is that typical DRIs and atypical DRIs stabilize the DAT in different conformations, with typical DRIs resulting in an outward-facing open conformation that produces differing pharmacological effects from those of atypical DRIs.[6][5][79][83]

Monoaminergic activity enhancers

Some MRAs, like the amphetamines amphetamine and methamphetamine, as well as trace amines like phenethylamine, tryptamine, and tyramine, are additionally monoaminergic activity enhancers (MAEs).[8][9][84] That is, they enhance the action potential-mediated release of monoamine neurotransmitters (in contrast to MRAs, which induce uncontrolled monoamine release independent of neuronal firing).[8][9][84] They are usually active as MAEs at much lower concentrations than those at which they induce monoamine release.[8][9][84] The MAE actions of MAEs may be mediated by TAAR1 agonism, which has likewise been implicated in monoamine-releasing actions in some studies.[85][86][87] MAEs without concomitant potent monoamine-releasing actions, like selegiline (L-deprenyl), phenylpropylaminopentane (PPAP), and benzofuranylpropylaminopentane (BPAP), have been developed.[8][9]

Endogenous MRAs

A number of endogenous compounds are known to act as MRAs.[4][88][77][11][5] These include the monoamine neurotransmitters dopamine (an DRA),[88] norepinephrine (an NRA),[88] and serotonin (an SRA) themselves,[88] as well as the trace amines phenethylamine (an NDRA),[5][84][89][90] tryptamine (an SDRA or imbalanced SNDRA),[77][11] and tyramine (an NDRA).[88][4] Synthetic MRAs are substantially based on structural modification of these endogenous compounds, most prominently including the substituted phenethylamines and substituted tryptamines.[88][2][3][77][91][92][93]

Release of monoamine neurotransmitters by themselves, for instance in the cases of serotonin, norepinephrine, and dopamine, has been referred to as "self-release".[4] The physiological significance of the findings that monoamine neurotransmitters can act as releasing agents of themselves is unclear.[4] However, it could imply that efflux is a common neurotransmitter regulatory mechanism that can be induced by any transporter substrate.[4]

It is possible that monoamine neurotransmitter self-release could be a protective mechanism.[4][94] It is notable in this regard that intracellular non-vesicular or cytoplasmic dopamine is toxic to neurons and that the vesicular monoamine transporter 2 (VMAT2) is neuroprotective by packaging this dopamine into synaptic vesicles.[95][96][97][94] Along similar lines, MRAs induce the efflux of non-vesicular monoamine neurotransmitter and thereby move cytoplasmic neurotransmitter into the extracellular space.[5] On the other hand, many MRAs but not all also act as VMAT2 inhibitors and reversers, and hence concomitantly induce the release of vesicular monoamine neurotransmitters like dopamine into the cytoplasm.[5] Induction of VMAT2 efflux by MRAs appears to be related to their monoaminergic neurotoxicity.[35][98][29]

Monoaminergic neurotoxicity

Some MRAs have been found to act as monoaminergic neurotoxins and hence to produce long-lasting damage to monoaminergic neurons.[99][100] Examples include dopaminergic neurotoxicity with amphetamine and methamphetamine and serotonergic neurotoxicity with methylenedioxymethamphetamine (MDMA).[99][100] Amphetamine may produce significant dopaminergic neurotoxicity even at therapeutic doses.[101][102][103][104][105][106] However, clinical doses of amphetamine producing neurotoxicity is controversial and disputed.[107][101][103] In contrast to amphetamines, monoamine reuptake inhibitors like methylphenidate lack apparent neurotoxic effects.[101]

Analogues of MDMA with retained MRA activity but reduced or no serotonergic neurotoxicity, like 5,6-methylenedioxy-2-aminoindane (MDAI) and 5-iodo-2-aminoindane (5-IAI), have been developed.[28][108] Certain drugs have been found to block the neurotoxicity of MRAs in animals.[100] For instance, the selective MAO-B inhibitor selegiline has been found to prevent the serotonergic neurotoxicity of MDMA in rodents.[100]

Chemical families

MRAs are usually arylalkylamines. A number of different structural families of compounds have been found to act as MRAs. The possible structural forms of MRAs are limited by a small molecular size requirement for activity.[5] Molecules that are too large become monoamine reuptake inhibitors as they can no longer be transported into neurons by the monoamine transporters and induce monoamine release intracellularly.[5]

Phenethylamine-like

Amine fused into ring

Alkyl chain fused into ring

Tryptamine-like

Ring-less (alkylamines)

Chemical family structure examples of monoamine releasing agents

Activity profiles

The activities of many MRAs in terms of their potencies, efficacies, and selectivities for monoamine release induction in vitro have been characterized in numerous studies in the scientific literature.[2][71][3][5][149] These studies have been especially conducted by the research lab led by Richard B. Rothman and Michael H. Baumann at the National Institute on Drug Abuse (NIDA).[2][71][3][149] These researchers developed an assay measuring monoamine release from rat brain synaptosomes in 1999 that has subsequently been widely employed.[149][71][88][150][151] The data with this procedure from many relevant studies are provided in the table below.[2][3] The Rothman and Baumann lab refers to these data as the "Phenyl Amine Library", "Phenethylamine Library", "Phenylethylamine Library", or "PAL" library, a large library of values of phenethylamine analogs at the monoamine transporters (1,400 compounds as of 2015), and has designated PAL-# code names for the drugs included in it.[152][5][149]

Another method of measuring monoamine release involves the use of human HEK293 cells transfected with and expressing monoamine transporters.[51][58][28][153][110] However, MRAs show differing and much lower potencies in this system compared to rat brain synaptosomes, and it is much less frequently employed.[51][58][28][153][110] The reasons for these differences are not entirely clear, but may be related to species differences, differences in release assay methods, and/or absence of important neuronal membrane proteins in non-neuronal HEK293 cells.[110][50]

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Activity profiles of monoamine releasing agents in rat brain synaptosomes (EC50, nM)[2][3][4]
Compound PAL # 5-HT NE DA Type Class Ref
1-Methyl-T PAL-637 53.1 >10000 >10000 SRA Tryptamine [11]
1-Phenylpiperazine (PP) ND 880 186 2530 SNRA Phenylpiperazine [131]
1ZP2MA ND ND ND 61.9 ND Indolizinylethylamine [139]
2-Aminoindane (2-AI, AI) ND >10000 86 439 NDRA 2-Aminoindane [33]
2-APBT ND 8.9 21.6 38.6 SNDRA APBT [117]
2-BMC ND 2837 156 650 NDRA Cathinone [154]
2-CA ND ND 19.1 62.4 ND Amphetamine [4]
2-CMC ND 2815 93 179 NDRA Cathinone [154]
2-FA ND ND 24.1 38.1 ND Amphetamine [4]
2-FMA ND ~15000 <100 ~90 NDRA Amphetamine - 2-FMC ND >10000 ND
(85% at 10 μM)		 48.7 NDRA Cathinone [137]
2-FPM ND 4808 28 112 NDRA Phenylmorpholine [155]
2-MA ND ND 37 127 ND Amphetamine [4]
2-MeO-A ND ND 473 1478 ND Amphetamine [4]
2-MeO-MC ND 7220 339 920 NDRA Cathinone [154]
2-MMC ND 347–490 53 81–97.9 SNDRA Cathinone [137][154]
2-MPM ND 1758 102 374 NDRA Phenylmorpholine [156]
2-Phenylmorpholine PAL-632 20260
(31% at 10 μM)		 79
(96% at 10 μM)		 86
(98% at 10 μM)		 NDRA Phenylmorpholine [157]
2-TFMeO-MC ND >10000 ND
(33% at 10 μM)		 >10000 IA Cathinone [137]
2-TFMMC (2-TFMAP) ND 8400–>10000 2200
(69% at 10 μM)		 8000–>10000 SNDRA Cathinone [158][137][159][154]
2C-C ND >100000 >100000 100000 IA Phenethylamine [109][160]
2C-D ND IA IA IA IA Phenethylamine [160]
2C-E ND >100000 >100000 >100000 IA Phenethylamine [109][160]
2C-I ND >100000 >100000 >100000 IA Phenethylamine [109][160]
2C-T-2 ND IA IA IA IA Phenethylamine [160]
3-APBT ND 21.9 13.4 21.7 SNDRA APBT [117]
3-BCPC PAL-586 621 ND IA (RI) ND Cathinone [152]
3-BMC ND 136–137 25 21–28.0 SNDRA Cathinone [137][161][154]
3-CA PAL-304 120 9.4 11.8 SNDRA Amphetamine [123][4][152][162]
3-CC ND 567 105 64 SNDRA Cathinone [163][161]
3-CCPC (RTI-6037-39) PAL-433 1328 ND IA (RI) ND Cathinone [152][164]
  (–)-3-CCPC PAL-1122 562 ND IA (RI) ND Cathinone [152]
  (+)-3-CCPC PAL-1123 733 ND IA (RI) ND Cathinone [152]
3-CEC PAL-361 IA ND IA ND Cathinone [152]
3-Cl-4-Me-CPC PAL-820 181 ND IA (RI) ND Cathinone [152]
3′-Cl-5-Me-PM PAL-738 23
(Emax = 96%)		 65
(Emax = 89%)		 58
(Emax = 78%)		 SNDRA Phenylmorpholine [76][165]
3-CMC (clophedrone) PAL-434 211–410 19–54.4 26–46.8 SNDRA Cathinone [5][137][161][154][152][166]
3-CPC PAL-363 IA ND IA (RI) ND Cathinone [152]
3′-CPM PAL-594 301 75
(82% at 10 μM)		 27
(100% at 10 μM)		 ND Phenylmorpholine [165][157]
3-FA PAL-353 1937 16.1 24.2 NDRA Amphetamine [167][4]
3-FMC ND 1460 ND
(100% at 10 μM)		 64.8 NDRA Cathinone [137]
3′-FPM PAL-593 1269–2558 17–30 43–60 NDRA Phenylmorpholine [155][157]
3-MA PAL-314 218 18.3 33.3 NDRA Amphetamine [167][123][4]
3-MCPC PAL-588 1067 ND IA (RI) ND Cathinone [152]
3-MeO-A ND ND 58.0 103 ND Amphetamine [4]
3-MeO-CPC PAL-591 1014 ND IA (RI) ND Cathinone [152]
3-MeO-MC ND 306–683 111
(68% at 10 μM)		 109–129 SNDRA Cathinone [137][161][154]
3-MeO-PM PAL-823 ND
(78% at 10 μM)		 ND
(86% at 10 μM)		 ND
(96% at 10 μM)		 ND Phenylmorpholine [157]
3-MMC ND 268–292 27 28–70.6 SNDRA Cathinone [5][137][161][154]
3-MPM PAL-773 5383 509 1321 SNDRA Phenylmorpholine [156]
3-TFMeO-MC ND 188 ND
(79% at 10 μM)		 729 SNDRA Cathinone [137]
3-TFMMC (3-TFMAP) ND 297–380 2700
(78% at 10 μM)		 610–1290 SNDRA Cathinone [158][137][159][154]
3,4-DCCPC PAL-787 356 ND IA (RI) ND Cathinone [152]
4-APBT ND 21.2 46.2 66.6 SNDRA APBT [117]
4-Benzylpiperidine ND 5246 41.4 109 NDRA Benzylpiperidine [168]
4-BMC (brephedrone) ND 42.5–60.2 100 59.4 SNDRA Cathinone [169][137][161][154][170][171]
4-CA (PCA) ND 28.3 23.5–26.2 42.2–68.5 SNDRA Amphetamine [123][4][172][173]
4-CC ND 128.4 85.1 221.8 SNDRA Cathinone [172]
4-CCPC PAL-743 1632 ND IA (RI) ND Cathinone [152]
4-CEA (PCEA) ND 33.8 162.6 238.0 SNDRA Amphetamine [172][173]
4-CEC ND 152.6 5194.0 353.6 SDRA Cathinone [172]
4-CMA (PCMA) ND 29.9 36.5 54.7 SNDRA Amphetamine [172][173]
4-CMC (clephedrone) ND 71.1–144 44–90.9 42.2–74.7 SNDRA Cathinone [169][137][172][161][154][170][171]
4-Et-PEA PAL-505 ND ND 2087 ND Phenethylamine [5]
4-FA PAL-303 730–939 28.0–37 51.5–200 NDRA Amphetamine [167][109][123][4]
4-Fluoro-T PAL-551 108 1123 106 SDRA Tryptamine [11]
4-FMC (flephedrone) ND 1290–1450 62 83.4–119 NDRA Cathinone [169][137][161][170][171]
4-FPM PAL-635 2403
(88% at 10 μM)		 285
(100% at 10 μM)		 529
(95% at 10 μM)		 SNDRA Phenylmorpholine [157]
4′-FPM PAL-748 1895 58 191 NDRA Phenylmorpholine [155][157]
4-iPr-PEA PAL-595 ND ND IA ND Phenethylamine [5]
4-MA PAL-313 53.4 22.2 44.1 SNDRA Amphetamine [167][123][4]
4-MAR ND ND ND ND ND Phenyloxazolamine [153]
  cis-4-MAR ND 53.2 4.8 1.7 NDRA Phenyloxazolamine [153][174]
4-MBA ND IA IA IA IA Amphetamine [175]
4-MCPC PAL-744 667 ND IA (RI) ND Cathinone [152]
4-MEA ND 102 182 550 SNDRA Amphetamine [175]
4-MeO-MC (methedrone) ND 120–195 111 506–881 SNDRA Cathinone [169][137][161][154][171]
4-MeO-T PAL-548 4114 >10000 >10000 SRA Tryptamine [11]
4-MMA ND 67.4 66.9 41.3 SNDRA Amphetamine [175][170]
4-MPA ND 650 752 IA SNRA Amphetamine [175]
4-MPEA (4-Me-PEA) PAL-503 ND ND 271 ND Phenethylamine [5]
4-MPM PAL-747 86 62 227 SNDRA Phenylmorpholine [156][157]
4-MTA ND ND ND ND ND Amphetamine [176][177][178]
4-MTMA PAL-1063 21 ND ND ND Amphetamine [76]
4-TFMeO-MC ND 118 ND 7510 ND Cathinone [137]
4-TFMMC (4-TFMAP) ND 190–270 900 2700–4230 SNRA Cathinone [179][169][158][159][171][154]
4,4'-DMAR ND ND ND ND SNDRA Phenyloxazolamine ND
  cis-4,4'-DMAR ND 17.7–59.9 11.8–31.6 8.6–24.4 SNDRA Phenyloxazolamine [174][180][153]
  trans-4,4'-DMAR ND 59.9 31.6 24.4 SNDRA Phenyloxazolamine [180][153]
5-APB ND 19 21 31 SNDRA Amphetamine [113]
5-APBT ND 10.3 38.4 92.8 SNDRA APBT [117]
5-API (5-IT) PAL-571 28–104.8 13.3–79 12.9–173 SNDRA Amphetamine [12][118]
5-Bromo-T PAL-518 75.0 >10000 478 SDRA Tryptamine [11]
5-Chloro-αET PAL-526 33.2 >10000 IA (RI) SRA α-Ethyltryptamine [11]
5-Chloro-αMT PAL-542 16.2 3434 54.3 SDRA α-Methyltryptamine [11][12]
5-Chloro-T PAL-441 19.1 >10000 476 SRA Tryptamine [11]
5-Fluoro-αET PAL-545 36.6 5334 150 SDRA α-Ethyltryptamine [11]
5-Fluoro-αMT PAL-544
PAL-212		 14–19 78–126 32–37 SNDRA α-Methyltryptamine [12][11][77]
5-Fluoro-T PAL-284 10.1 464 82.3 SDRA Tryptamine [11]
5-MABB (5-MBPB) ND ND ND ND ND Amphetamine [116][181]
  (S)-5-MABB ND 31 158 210 SNDRA Amphetamine [116][181]
  (R)-5-MABB ND 49 850 IA SRA Amphetamine [116][181]
5-MAPB ND 64–90 24 41–459 SNDRA Amphetamine [113][182]
  (S)-5-MAPB ND 67 ND 258 ND Amphetamine [182]
  (R)-5-MAPB ND 184 ND 1951 ND Amphetamine [182]
5-MeO-αMT ND 460 8900 1500 SNDRA α-Methyltryptamine [109]
5-MeO-DALT ND >100000 >100000 >100000 IA Tryptamine [109]
5-MeO-DET ND IA (RI) IA IA SRI Tryptamine [77]
5-MeO-DiPT ND >100000 (RI) >100000 (RI) >100000 IA Tryptamine [109][77]
5-MeO-DMT ND >100000 (RI) >100000 (RI) >100000 IA Tryptamine [109][77]
5-MeO-DPT ND IA (RI) IA IA (RI) SRI Tryptamine [77]
5-MeO-MiPT ND >100000 >100000 >100000 IA Tryptamine [109][77]
5-MeO-NET ND 284 >10000 >10000 SRA Tryptamine [77]
5-MeO-NiPT ND IA (RI) IA IA SRI Tryptamine [77]
5-MeO-NMT ND 1114 >10000 >10000 SRA Tryptamine [77]
5-MeO-T PAL-234 2169 >10000 11031 SDRA Tryptamine [11][77]
5-Methyl-T PAL-22 139 >10000 >10000 SRA Tryptamine [11]
6-APB ND 36 14 10 SNDRA Amphetamine [113]
6-APBT ND 10.7 13.6 7.2 SNDRA APBT [117]
6-API (6-IT) ND 19.9 25.6 164.0 SNDRA Amphetamine [118]
6-Fluoro-T PAL-227 4.4 1575 106 SRA Tryptamine [11]
6-MABB (6-MBPB) ND ND ND ND ND Amphetamine [116][181]
  (R)-6-MABB ND 172 227 IA SNRA Amphetamine [116][181]
  (S)-6-MABB ND 54 77 41 SNDRA Amphetamine [116][181]
6-MAPB ND 33 14 20 SNDRA Amphetamine [113]
6-MeO-T PAL-263 53.8 465 113 SNDRA Tryptamine [11]
6-Methyl-T PAL-522 51.6 >10000 353 SDRA Tryptamine [11]
7-APBT ND 36.9 28.5 16.8 SNDRA APBT [117]
7-Chloro-T PAL-532 8.03 656 1330 SRA Tryptamine [11]
7-MeO-T PAL-533 44.6 5600 2118 SRA Tryptamine [11]
7-Methyl-T PAL-286 23.7 >10000 3380 SRA Tryptamine [11]
α-Ethyltryptamine (AET, αET) PAL-125 23.2 640 232 SDRA α-Ethyltryptamine [11]
  (–)-α-Ethyltryptamine PAL-640 54.9 3670 654 SRA α-Ethyltryptamine [11]
  (+)-α-Ethyltryptamine PAL-647 34.7 592 57.6 SDRA α-Ethyltryptamine [11]
α-Me-MC (βk-mephentermine; RAD-081) ND 12860 153 590 NDRA Cathinone [183][184][185]
α-Methylisotryptamine (isoAMT) PAL-569 177 81 1062 SNRA Isotryptamine [12]
α-Methyltryptamine (αMT; AMT) PAL-17 21.7–68 79–112 78.6–180 SNDRA α-Methyltryptamine [109][11][186]
βk-NMPEA (FTS-096) ND >60000 148 1860 NRA Phenethylamine [183][184][185]
AMAPN ND 21 ND 55 ND Cathinone [137][187]
Amfepramone (diethylpropion) ND >10000 >10000 >10000 PD Cathinone [188][151]
Aminorex ND 193–414 15.1–26.4 9.1–49.4 SNDRA Phenyloxazolamine [88][174][4][153][151]
Amphetamine (A) ND ND ND ND NDRA Amphetamine ND
  Dextroamphetamine ND 698–1765 6.6–10.2 5.8–24.8 NDRA Amphetamine [88][189][4][190][151]
  Levoamphetamine ND ND 9.5 27.7 NDRA Amphetamine [123][4][191][192]
APPEA (α-Pr-PEA) PAL-550 IA ND IA (RI) ND Amphetamine [5][152]
BDB ND 180 540 2,300 SNRA Amphetamine [109]
Benzylpiperazine (BZP) ND 6050–>10000 62–68 175–600 NDRA Benzylpiperazine [109][193][3][4][194]
BK-NM-AMT ND 41.3 ND
(55% at 10 μM)		 92.8 SDRA α-Methyltryptamine [137][187][138]
BK-5F-NM-AMT ND 190 ND 620 ND α-Methyltryptamine [195]
BK-5Cl-NM-AMT ND 200 ND 865 ND α-Methyltryptamine [195]
BK-5Br-NM-AMT ND 295 ND 2100 ND α-Methyltryptamine [195]
BMAPN ND 27 ND
(94% at 10 μM)		 34 SNDRA Cathinone [137][187]
BMPEA (β-Me-PEA) ND ND 126 627 ND Phenethylamine [196]
Bufotenin (DMS, 5-HO-DMT) ND 30.5 >10000 >10000 SRA Tryptamine [77]
Buphedrone (βk-MEPEA) PAL-429 IA ND 411 ND Cathinone [152]
Bupropion (amfebutamone) ND IA (RI) IA (RI) IA (RI) NDRI Cathinone [185][163][161]
Butylamphetamine (NBA, BA) PAL-90 ND ND IA ND Amphetamine [5]
Butylone (βk-MBDB) ND 330 IA (RI) IA (RI) SRA/NDRI Cathinone [197][198]
Cathinone (C; βk-AMPH) ND 6100–7595 23.6–25.6 34.8–83.1 NDRA Cathinone [4][137][172]
  D-Cathinone ND >10000 72.0 183.9 NDRA Cathinone [199]
  L-Cathinone ND 2366–9267 12.4–28 18–24.6 NDRA Cathinone [200][163][199]
Chlorphentermine ND 18.2–30.9 >10000 (RI) 935–2650 SRA Amphetamine [88][151]
DEPEA (α-Et-EPEA) ND ND 209 604 ND Amphetamine [201]
Dibutylone ND IA IA (RI) IA (RI) DRI Cathinone [202]
Diethyltryptamine (DET) ND IA (RI) IA IA SRI Tryptamine [77]
Diisopropyltryptamine (DiPT) ND IA (RI) IA (RI) IA SRI Tryptamine [77]
Dimethylamphetamine ND ND 223 1250 ND Amphetamine [196]
Dimethyltryptamine (DMT) ND 81–114
(Emax = 81%)		 4166 >10000 SRA Tryptamine [77][78]
Dipropyltryptamine (DPT) ND >100000 (RI) >100000 (RI) >100000 (RI) IA Tryptamine [109][77]
DMPP (2,3-DMPP) PAL-218 24–26
(Emax = 85%)		 13.7–56
(Emax = 62%)		 1207–1320
(Emax = 66%)		 SNRA Phenylpiperazine [76][131]
DMPPA (β,N,N-TMPEA) ND ND 1337
(Emax = 67%)		 IA NRA Phenethylamine [196]
DOC ND IA IA IA IA Amphetamine [160]
DOM ND IA IA IA IA Amphetamine [203]
Dopamine (DA) ND >10000 (RI) 66.2 86.9 NDRA Phenethylamine [88][4]
EDMA ND 117 325 597 SNDRA Amphetamine [110][170]
EDMC ND 347 327 496 SNDRA Cathinone [110][170]
ENAP PAL-1045 12 137 46 SDRA Amphetamine [76]
Ephedrine (racephedrine) ND ND ND ND NDRA Cathinol ND
  D-Ephedrine (ephedrine) ND >10000 43.1–72.4 236–1350 NDRA Cathinol [88][4]
  L-Ephedrine ND >10000 218 2104 NRA Cathinol [88][200]
Ephylone ND IA (RI) IA (RI) IA (RI) IA (NDRI) Cathinone [204]
Epinephrine ND ND ND ND NDRA Phenethylamine ND
Ethcathinone (EC) ND 1923–2118 88.3–99.3 267.6–>1000 NRA Cathinone [188][4][172][190]
Ethylamphetamine (EA) PAL-99 ND ND 88.5 ND Amphetamine [5]
  S(+)-Ethylamphetamine ND 333.0 28.8 44.1 NDRA Amphetamine [172][173]
Ethylone (βk-MDEA) ND 617.4 4251 1122 SNDRA Cathinone [170]
Eutylone (βk-EBDB) ND 1020 IA (RI) IA (RI) SRA/NDRI Cathinone [202]
Fenfluramine (3-TFM-EA) ND 79.3–108 739 >10000 (RI) SRA Amphetamine [88][205][206][4]
  D-Fenfluramine ND 51.7 302 >10000 SNRA Amphetamine [88][205]
  L-Fenfluramine ND 147 >10000 >10000 SRA Amphetamine [205][72]
HHA ND ND 33 3485 ND Amphetamine [4]
HHMA ND 1729 77 130 NDRA Amphetamine [4][207]
HHMC ND 14100 110 90 NDRA Cathinone [208]
HMA ND 897 694 1450–3423 SNDRA Amphetamine [4][209][210]
HMMA ND 589–607 625 607–3652 SNDRA Amphetamine [4][209][210][207]
HMMC ND 7210 6340 5840 SNDRA Cathinone [208]
MBDB ND 540 3300 >100000 SNRA Amphetamine [109]
mCPP (3-CPP, 3CPP) ND 28–38.1 ≥1400 63000 SRA Phenylpiperazine [109][72][73]
MDA ND 160–162 47–108 106–190 SNDRA Amphetamine [206][4][113]
  (R)-MDA ND 310 290 900 SNDRA Amphetamine [206][4]
  (S)-MDA ND 100 50.0 98.5 SNDRA Amphetamine [206][4]
MDAI ND 114 117 1334 SNRA 2-Aminoindane [33]
MDC ND 966 394 370 SNDRA Cathinone [208]
MDEA PAL-192 47 2608 622 SNDRA Amphetamine [76]
  (R)-MDEA PAL-193 52 651 507 SNDRA Amphetamine [76]
  (S)-MDEA PAL-194 465 RI RI SRA Amphetamine [76]
MDDMA ND 588.8 IA IA SRA Amphetamine [211]
MDMA ND 50–85 54–110 51–278 SNDRA Amphetamine [88][212][118][206][113]
  (R)-MDMA ND 340 560 3700 SNDRA Amphetamine [206][4]
  (S)-MDMA ND 74 136 142 SNDRA Amphetamine [206][4]
MDMAR ND ND ND ND SNDRA Phenyloxazolamine ND
  cis-MDMAR ND 43.9 14.8 10.2 SNDRA Phenyloxazolamine [180]
  trans-MDMAR ND 73.4 38.9 36.2 SNDRA Phenyloxazolamine [180]
MDPV ND IA 13
(Emax = 24%)		 2.3
(Emax = 24%)		 NDRI Phenylethylpyrrolidine [189][170]
MDTMA ND IA IA IA IA Amphetamine [211]
MEAI (5-MeO-AI) ND 134 861 2646 SNRA 2-Aminoindane [33]
MEPEA (α-Et-MPEA) PAL-426 4698 58 179–225 NDRA Amphetamine [152][201]
Mephedrone (4-MMC) ND 118.3–122 58–62.7 49.1–51 SNDRA Cathinone [212][189][137][154][171]
  S(–)-Mephedrone ND 61 ND 74 ND Cathinone [190][213]
  R(+)-Mephedrone ND 1470 ND 31 ND Cathinone [190][213]
Mesocarb ND ND ND >100000 (RI) DRI Amphetamine [214]
Methamphetamine (MA) ND ND ND ND NDRA Amphetamine ND
  Dextromethamphetamine ND 736–1292 12.3–14.3 8.5–40.4 NDRA Amphetamine [88][212][4][151]
  Levomethamphetamine ND 4640 28.5 416 NRA Amphetamine [88][4]
Methcathinone (MC) ND 2592–5853 22–26.1 12.5–49.9 NDRA Cathinone [4][137][161][154][172]
  D-Methcathinone ND IA ND ND NRA Cathinone [185]
  L-Methcathinone ND 1772 13.1 14.8 NDRA Cathinone [200][190]
Methiopropamine ND IA (RI) IA (RI) IA (RI) NDRI Thiopropamine [215][216]
Methylone (MDMC) ND 234–708 140–270 117–220 SNDRA Cathinone [212][189][170][202][208]
Methylphenidate ND IA (RI) IA (RI) IA (RI) NDRI Phenidate [3][35][217]
Methylethyltryptamine (MET) ND 182.7 ND ND ND Tryptamine [78]
Mexedrone (4-MMC-MeO) ND 2525 IA (RI) IA (RI) SRA/NDRI Cathinone [218]
MiPT ND IA IA IA IA Tryptamine [77]
MMAI ND 31 3101 >10000 SRA 2-Aminoindane [33]
MNAP (methamnetamine) PAL-1046 13 34 10 SNDRA Amphetamine [76][5]
MPPA (BMMPEA, β-Me-NMPEA) ND ND 154 574 ND Phenethylamine [196]
Naphthylisopropylamine (NAP) PAL-287 3.4 11.1 12.6 SNDRA Amphetamine [219][4]
Naphthylmetrazine PAL-704 IA (RI) 203 111 NDRA/SRI Phenylmorpholine [157]
Naphthylmorpholine PAL-678 ND
(92% at 10 μM)		 ND
(88% at 10 μM)		 ND
(79% at 10 μM)		 ND Phenylmorpholine [157]
NET (NETP; N-Et-T) PAL-536 18.6 IA (RI) IA (RI) SRA Tryptamine [11][77]
NiPT ND IA (RI) IA IA SRI Tryptamine [77]
NMT PAL-152 22.4 733 321 SRA Tryptamine [11][77]
Norephedrine (phenylpropanolamine) ND ND ND ND NDRA Cathinol ND
  D-Norephedrine ND >10000 42.1 302 NDRA Cathinol [200]
  L-Norephedrine ND >10000 137 1371 NRA Cathinol [200]
Norepinephrine (NE) ND >10000 164 869 NDRA Phenethylamine [88][4]
Norfenfluramine (3-TFMA) ND 104 168–170 1900–1925 SNRA Amphetamine [205][206]
  (+)-Norfenfluramine ND 59.3 72.7 924 SNRA Amphetamine [205]
  (–)-Norfenfluramine ND 287 474 >10000 SNRA Amphetamine [205]
Normephedrone (4-MC) ND 210 100 220 SNDRA Cathinone [220][199][190]
  R(+)-Normephedrone ND 179 89 150 SNDRA Cathinone [190][199]
  S(–)-Normephedrone ND 1592 115 391 NDRA Cathinone [190][199]
Norpropylhexedrine ND ND ND ND NDRA Cyclohexylethylamine ND
Norpseudoephedrine ND ND ND ND NDRA Cathinol ND
  D-Norpseudoephedrine (cathine) ND >10000 15.0 68.3 NDRA Cathinol [200]
  L-Norpseudoephedrine ND >10000 30.1 294 NDRA Cathinol [200]
ODMA ND ND ND ND SNDRA Amphetamine [121]
oMPP (2-MPP) PAL-169 175 39.1 296–542 SNDRA Phenylpiperazine [221][5][131]
PMA (4-MeO-A) ND ND 166 867 SNDRA Amphetamine [4][136][178]
PMMA (4-MeO-MA) ND ND ND ND SNDRA Amphetamine [178]
  (S)-PMMA ND 41 147 1000 SNRA Amphetamine [179][222][136]
  (R)-PMMA ND 134 >14000 1600 SRA Amphetamine [179][222][136]
Pentylone ND 476–1030
(Emax ≈ 50%)		 IA (RI) IA (RI) SRA/NDRI Cathinone [197][202][204]
Phenacylamine (βk-PEA) PAL-27 >10000 ND
(96% at 10 μM)		 208 NDRA Phenethylamine [5][137][190]
Phendimetrazine ND >100000 >10000 >10000 PD Phenylmorpholine [223][4][151]
Phenethylamine (PEA) ND >10000 10.9 39.5 NDRA Phenethylamine [5][123][4]
Phenmetrazine (PM) PAL-55 7765–>10000 29–50.4 70–131 NDRA Phenylmorpholine [223][4][156][157]
  (+)-Phenmetrazine ND 3246 37.5 87.4 NDRA Phenylmorpholine [223]
  (–)-Phenmetrazine ND >10000 62.9 415 NDRA Phenylmorpholine [223]
Phentermine (P, PH) ND 2575–3511 28.8–39.4 262 NDRA Amphetamine [88][4][151]
Phenylalaninol ND ND ND ND ND Amphetamine ND
  D-Phenylalaninol PAL-329 >10000 106 1355 NRA Amphetamine [221]
Phenylbutenamine ND ND ND ND ND Phenylbutenamine ND
  (3E)-Phenylbutenamine PAL-881 >10000 308 666 NDRA Phenylbutenamine [127][128]
  (3Z)-Phenylbutenamine PAL-893 >10000 301 1114 NDRA Phenylbutenamine [127][128]
Phenylbutynamine PAL-874 >10000 305 688 NDRA Phenylbutynamine [76]
Phenylisobutylamine (α-Et-PEA, AEPEA) ND 4698 80 225–273 NDRA Amphetamine [5][152][162][201]
Phenylpropylamine ND ND 222 1491 NDRA Phenylpropylamine [123][4]
pMeOPP (4-MeOPP) ND 3200 440–1500 6300–11000 SNRA Phenylpiperazine [109][131]
pMPP (4-MPP) PAL-233 220 >10000 >20000 SRA Phenylpiperazine [131][5]
pNPP (4-NPP) PAL-175 19–43
(Emax = 57%)		 >10000 >10000 SRA Phenylpiperazine [76][131]
Propylamphetamine (PA) PAL-424 ND ND RI (1013) ND Amphetamine [5]
Propylcathinone (PC) PAL-359 ND ND IA ND Cathinone [5][190]
Propylhexedrine ND ND ND ND NDRA Cyclohexylethylamine ND
Propylone ND 3128 IA (RI) 975.9 SDRA Cathinone [170]
Pseudoephedrine (racemic) ND ND ND ND NDRA Cathinol ND
  D-Pseudoephedrine ND >10000 4092 9125 NDRA Cathinol [200]
  L-Pseudoephedrine (pseudoephedrine) ND >10000 224 1988 NRA Cathinol [200]
Pseudophenmetrazine ND >10000 514 IA (RI) NRA/DRI Phenylmorpholine [223]
  (+)-Pseudophenmetrazine ND >10000 349 1457 NDRA Phenylmorpholine [223]
  (–)-Pseudophenmetrazine ND >10000 2511 IA (RI) NRA/DRI Phenylmorpholine [223]
Psilocin PAL-153 561
(Emax = 54%)		 >10000 >10000 SRA Tryptamine [76][77]
SeDMA ND ND ND ND SNDRA Amphetamine [121]
Serotonin (5-HT) ND 44.4 >10000 (RI) ≥1960 SRA Tryptamine [88][4]
TDMA ND ND ND ND SNDRA Amphetamine [121]
TFMCPP (3-TFM-4-C-PP) PAL-179 33
(Emax = 66%)		 >10000 >10000 SRA Phenylpiperazine [76]
TFMPP (3-TFMPP) ND 121 >10000 >10000 SRA Phenylpiperazine [193][194][4]
TMA (3,4,5-TMeO-A) ND 16000 >100000 >100000 SRA Amphetamine [109]
TMA-2 (2,4,5-TMeO-A) ND >100000 >100000 >100000 IA Amphetamine [109]
TMA-6 (2,4,6-TMeO-A) ND >100000 >100000 >100000 IA Amphetamine [109]
Tramadol ND IA (RI) IA (RI) IA SNRI ND [3]
Tryptamine (T) PAL-235 32.6 716 164 SDRA Tryptamine [77][11]
Tyramine ND 2775 40.6 119 NDRA Phenethylamine [88][4]
Notes: (1) The smaller the value, the more potently the substance releases the neurotransmitter. (2) These values were from assays conducted using rat brain synaptosomes. Values from other methods of quantifying monoamine release, such as HEK293 cells transfected with monoamine transporters, are not fully analogous to neuronal cells and result in much different and lower potencies. As a result, they are not included in this table.

In addition to the potencies of MRAs in terms of their MRA activity, data on the affinities (Ki) of various MRAs for the monoamine transporters (MATs) and their potencies (IC50) in acting as monoamine reuptake inhibitors (MRIs) have been published.[2][88][223][224][205][189][211][187][172][175][225][226][116][158][218][163][117][227][131][156] Activities of MRAs at the vesicular monoamine transporter 2 (VMAT2) have been published as well.[27]

Notes

  1. ↑ MRAs that are inactive at VMAT2 include phentermine, phenmetrazine, and benzylpiperazine (BZP).[5][27] Others, including cathinones like mephedrone, methcathinone, and methylone, also show only weak VMAT2 activity (e.g., ~10-fold weaker than the corresponding amphetamines).[28][29][30]
  2. ↑ MRAs that are inactive at the human TAAR1 include most cathinones (e.g., methcathinone, mephedrone, flephedrone, and brephedrone), ephedrine, 4-methylamphetamine (4-MA), para-methoxyamphetamine (PMA), 4-methylthioamphetamine (4-MTA), MDMA MDEA, MBDB, 5-APDB, 5-MAPDB, 4-methylaminorex derivatives, meta-chlorophenylpiperazine (mCPP), TFMPP, and methylhexanamine (DMAA), among others.[52][53][26][50][58]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "Amphetamine, past and present--a pharmacological and clinical perspective". Journal of Psychopharmacology 27 (6): 479–496. June 2013. doi:10.1177/0269881113482532. PMID 23539642. "Although the pharmacological effect of amphetamine is predominantly mediated by monoamine release, this mechanism is complemented by reuptake inhibition [...] that combine additively or synergistically to augment synaptic monoamine concentrations. The description of amphetamine as a 'monoamine reuptake inhibitor' often causes some confusion, and the difference between the mechanisms of amphetamine, which is a competitive reuptake transport substrate, and classical reuptake inhibitors is illustrated in Figure 3. [...] d-Amphetamine is generally accepted to be a weak dopamine reuptake inhibitor with a Ki value of ~100 nM, a moderately potent inhibitor of noradrenaline reuptake (Ki = 40–50 nM) and a very weak inhibitor of 5-HT reuptake (Ki = 1.4-3.8 µM). [...] the efficacy of amphetamine relative to other indirect monoamine agonists, for example classical reuptake inhibitors, can only be estimated from in vivo experiments. [...] [d- and l-Amphetamine] dose-dependently increased the extracellular concentrations of noradrenaline in the prefrontal cortex (PFC) and dopamine in the striatum. The pharmacodynamics of their effects are typical of those reported for monoamine releasing agents, i.e. a fast onset of action with peak increases of noradrenaline and dopamine efflux occurring at 30–45 min, large effects (400–450% of baseline for noradrenaline and 700–1500% of baseline for dopamine), with a relatively rapid decline after the maximum (Figure 4). [...] the magnitude of the increases produced by amphetamine's isomers are greater than those reported for classical reuptake inhibitors such as atomoxetine or bupropion, and there is no dose-effect ceiling to amphetamine's actions [...] The primary action of amphetamine is to increase synaptic concentrations of monoamine neurotransmitters, thereby indirectly enhancing noradrenergic, dopaminergic neurotransmission in the CNS.". 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 "Monoamine transporters and psychostimulant drugs". European Journal of Pharmacology 479 (1–3): 23–40. October 2003. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 3.18 3.19 3.20 3.21 3.22 3.23 3.24 "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 4.19 4.20 4.21 4.22 4.23 4.24 4.25 4.26 4.27 4.28 4.29 4.30 4.31 4.32 4.33 4.34 4.35 4.36 4.37 4.38 4.39 4.40 4.41 4.42 4.43 4.44 4.45 4.46 4.47 4.48 4.49 4.50 4.51 4.52 4.53 4.54 4.55 "Dopamine-releasing agents". Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. July 2008. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf. 
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 5.11 5.12 5.13 5.14 5.15 5.16 5.17 5.18 5.19 5.20 5.21 5.22 5.23 5.24 5.25 5.26 5.27 5.28 5.29 5.30 5.31 5.32 5.33 5.34 5.35 5.36 5.37 5.38 5.39 5.40 5.41 5.42 5.43 5.44 "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug and Alcohol Dependence 147: 1–19. February 2015. doi:10.1016/j.drugalcdep.2014.12.005. PMID 25548026. "Converging lines of evidence have solidified the notion that DA releasers are substrates of the transporter and once translocated, they reverse the normal direction of transporter flux to evoke release of endogenous neurotransmitters. The nature of this reversal is not well understood, but the entire process is primarily transporter-dependent and requires elevated intracellular sodium concentrations, phosphorylation of DAT, and possible involvement of transporter oligomers (Khoshbouei et al., 2003, 2004; Sitte and Freissmuth, 2010). [...] A library of approximately 1400 phenethylamine compounds (PAL compounds) has been screened using these protocols. Among the active compounds, the smaller DAT ligands were found to be DA releasers while the sterically larger compounds were DAT uptake inhibitors. [...] Generic pharmacophore for biogenic amine transporter ligands. Note that transportable substrate ligands exhibit size constraints defined by the red circle. Functional groups attached to the nitrogen, α-carbon or phenyl ring that extend beyond the "edge" of the pharmacophore will generate partial substrates, transporter blockers or be inactive. [...] phenmetrazine was found to be completely inactive at VMAT2 indicating that a direct interaction of the releaser with VMAT2 is not required for inducing neurotransmitter efflux into the extracellular space (Partilla et al., 2006). Phentermine and benzylpiperazine were also found in the same study to lack VMAT2 activity (Table 5).". 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 "Nonclassical pharmacology of the dopamine transporter: atypical inhibitors, allosteric modulators, and partial substrates". The Journal of Pharmacology and Experimental Therapeutics 346 (1): 2–10. July 2013. doi:10.1124/jpet.111.191056. PMID 23568856. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 "Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine". Neuropharmacology 87: 19–40. December 2014. doi:10.1016/j.neuropharm.2014.06.012. PMID 24953830. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 "Pharmacological studies with endogenous enhancer substances: beta-phenylethylamine, tryptamine, and their synthetic derivatives". Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (3): 421–427. May 2004. doi:10.1016/j.pnpbp.2003.11.016. PMID 15093948. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 "Enhancer regulation/endogenous and synthetic enhancer compounds: a neurochemical concept of the innate and acquired drives". Neurochemical Research 28 (8): 1275–1297. August 2003. doi:10.1023/a:1024224311289. PMID 12834268. 
  10. ↑ "Dual dopamine/serotonin releasers as potential medications for stimulant and alcohol addictions". The AAPS Journal 9 (1): E1-10. January 2007. doi:10.1208/aapsj0901001. PMID 17408232. 
  11. ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 11.11 11.12 11.13 11.14 11.15 11.16 11.17 11.18 11.19 11.20 11.21 11.22 11.23 11.24 11.25 11.26 11.27 11.28 11.29 11.30 "Alpha-ethyltryptamines as dual dopamine-serotonin releasers". Bioorganic & Medicinal Chemistry Letters 24 (19): 4754–4758. October 2014. doi:10.1016/j.bmcl.2014.07.062. PMID 25193229. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 "Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys". Experimental and Clinical Psychopharmacology 22 (3): 274–284. June 2014. doi:10.1037/a0036595. PMID 24796848. 
  13. ↑ Neurological Aspects of Substance Abuse. Butterworth-Heinemann. 2004. pp. 117–. ISBN 978-0-7506-7313-6. https://books.google.com/books?id=fOfxoQm_a7MC&pg=PA117. 
  14. ↑ Competitive problems in the drug industry: hearings before Subcommittee on Monopoly and Anticompetitive Activities of the Select Committee on Small Business, United States Senate, Ninetieth Congress, first session. U.S. Government Printing Office. 1976. pp. 2–. https://books.google.com/books?id=Rs1GAQAAMAAJ&pg=RA2-PA56. 
  15. ↑ "Ecstasy (MDMA), amphetamine, and LSD: comparative mood profiles in recreational polydrug users" (in en). Human Psychopharmacology: Clinical and Experimental 12 (5): 501–504. 1 September 1997. doi:10.1002/(sici)1099-1077(199709/10)12:5<501::aid-hup913>3.3.co;2-m. ISSN 1099-1077. 
  16. ↑ "Effects of 5-HT-releasing agents on the extracellullar hippocampal 5-HT of rats. Implications for the development of novel antidepressants with a short onset of action". Neuropharmacology 38 (7): 1055–1061. July 1999. doi:10.1016/s0028-3908(99)00023-4. PMID 10428424. 
  17. ↑ "The drug effects questionnaire: psychometric support across three drug types". Psychopharmacology 227 (1): 177–192. May 2013. doi:10.1007/s00213-012-2954-z. PMID 23271193. 
  18. ↑ "Effect of rate of administration on subjective and physiological effects of intravenous cocaine in humans". Drug and Alcohol Dependence 82 (1): 19–24. March 2006. doi:10.1016/j.drugalcdep.2005.08.004. PMID 16144747. 
  19. ↑ "Pharmacodynamics and pharmacokinetics of single nasal (5 mg and 10 mg) and oral (50 mg) doses of ephedrine in healthy subjects". European Journal of Clinical Pharmacology 57 (6–7): 447–455. September 2001. doi:10.1007/s002280100317. PMID 11699608. 
  20. ↑ "Ephedra and its application to sport performance: another concern for the athletic trainer?". Journal of Athletic Training 36 (4): 420–424. October 2001. PMID 16558668. 
  21. ↑ "Central fatigue: the serotonin hypothesis and beyond". Sports Medicine 36 (10): 881–909. 1 January 2006. doi:10.2165/00007256-200636100-00006. PMID 17004850. 
  22. ↑ "Alterations in central fatigue by pharmacological manipulations of neurotransmitters in normal and high ambient temperature". Sports Medicine 40 (3): 229–246. March 2010. doi:10.2165/11533670-000000000-00000. PMID 20199121. 
  23. ↑ 23.00 23.01 23.02 23.03 23.04 23.05 23.06 23.07 23.08 23.09 23.10 23.11 23.12 23.13 23.14 23.15 23.16 23.17 23.18 23.19 23.20 23.21 23.22 23.23 "Molecular Mechanisms of Amphetamines". Substance Use Disorders. Handbook of Experimental Pharmacology. 258. 2020. 265–297. doi:10.1007/164_2019_251. ISBN 978-3-030-33678-3. "Despite the knowledge that amphetamine is a substrate for the DAT and NET, questions still remain as to the physiological mechanism of amphetamine action. [...] At lower doses, amphetamine preferentially releases a newly synthesized pool of DA. [...] DA stores will not be depleted by the AMPT in these short time frames, leading to the conclusion that newly synthesized DA is a principal substrate for amphetamine-stimulated DA efflux. [...] Controversy has surrounded the role of VMAT2 and synaptic vesicles in the mechanism of amphetamine action. [...] Undoubtedly vesicles contribute strongly to the maximal DA released by amphetamine, although VMAT2 is not absolutely required for amphetamine to release DA from nerve terminals (Pifl et al. 1995; Fon et al. 1997; Wang et al. 1997; Patel et al. 2003). [...] Recently, a new model of amphetamine action has been formulated that proposes that amphetamine elevates tonic DA (non-exocytotic) signaling through reverse transport and depleting vesicular stores, but activates phasic DA signaling by enhancing vesicular DA release from the readily releasable pool (Covey et al. 2013). These conclusions were drawn from experiments using fast-scan cyclic voltammetry in either freely moving or anesthetized rats (Avelar et al. 2013; Daberkow et al. 2013). Again, one must strongly consider the dose of amphetamine in interpretation of these actions (Calipari and Ferris 2013)." 
  24. ↑ 24.00 24.01 24.02 24.03 24.04 24.05 24.06 24.07 24.08 24.09 "Mechanisms of neurotransmitter release by amphetamines: a review". Prog Neurobiol 75 (6): 406–433. April 2005. doi:10.1016/j.pneurobio.2005.04.003. PMID 15955613. "While the sine qua non property of AMPH at monoamine transporters is the promotion of monoamine release via reverse transport, there are yet profound mysteries in understanding how this works. It is additionally clear that AMPH is an uptake blocker as well as a releaser, and differentiating between elevating extracellular monoamines by reverse transport or uptake blockade can be difficult. Of course, the many AMPH derivatives and different transporters maintain different combinatorial properties, an important topic beyond the range of this article. [...] The mechanism of how reverse transport occurs is unknown, and a very old issue of how reserpine can inhibit uptake but not halt reverse transport remains opaque.". 
  25. ↑ 25.0 25.1 25.2 25.3 "Amphetamines, new psychoactive drugs and the monoamine transporter cycle". Trends Pharmacol Sci 36 (1): 41–50. January 2015. doi:10.1016/j.tips.2014.11.006. PMID 25542076. "[...] most amphetamines are [monoamine transporter] substrates, which pervert the relay to elicit efflux of monoamines into the synaptic cleft. However, some amphetamines act as transporter inhibitors. [...] Amphetamines also bind to the trace amine receptors TAR1, [...] TAR1 is not activated by all psychoactive amphetamines (p-chloroamphetamine, for instance, is inactive); stimulation of TAR1 actually reduces dopamine release and thus decreases sensitivity to amphetamine [18,19]. [...] amphetamines are taken up by plasma-membrane monoamine transporters as exogenous substrates [31]. Accordingly, they inhibit the physiological monoamine reuptake in a competitive manner [36]. As a consequence of both amphetamine-induced reverse transport and inhibition of reuptake, the synaptic monoamine concentration increases, which in turn activates post- and presynaptic receptors [37]. The activation of postsynaptic receptors propagates the signal and contributes to the biological response. Stimulation of presynaptic autoreceptors decreases the quantal release of monoamines upon excitatory inputs; [...]". 
  26. ↑ 26.0 26.1 26.2 26.3 26.4 "A narrative review of the neuropharmacology of synthetic cathinones-Popular alternatives to classical drugs of abuse". Hum Psychopharmacol 38 (3). May 2023. doi:10.1002/hup.2866. PMID 36866677. "An interesting neurochemical issue is the interaction between compounds acting as blockers and substrates. [...] Substrates (e.g. mephedrone) use MAT proteins to release neurotransmitters, while inhibitors (e.g. [MDPV]) prevent the transport of any compounds through MATs. It follows that simultaneous use of a substrate and a blocker should result in an antagonistic mechanism that lowers the mutual potency. Paradoxically, MDPV and mephedrone occur together in mixtures, and in addition they reinforce each other's effects, resulting in very strong stimulation. Simultaneous use of both SCs is reported by users, and studies in rodents involving simultaneous administration of the drugs have shown a significant increase in locomotor activity and additive effect compared to administering these drugs alone (Allen et al., 2019; Benturquia et al., 2019). [...] The explanation for this phenomenon can be found in the action of organic cation transporter (OCT) proteins. OCTs are a family of proteins responsible for endothelial transport of small, organic, hydrophilic, and positively charged molecules, including neurotransmitters and xenobiotics (Couroussé & Gautron, 2015). OCT3 is a protein present in the dopaminergic regions of the central nervous system, where it promotes DA reuptake when it is inhibited for high affinity transporters (DAT) (Couroussé & Gautron, 2015). Monoamines can also be released by OCTs. [...] Ex vivo studies on superior cervical ganglia cells enriched in NET and OCT3 showed that in the presence of MDPV blocking MAT proteins, mephedrone causes neurotransmitter efflux through OCT3, which is insensitive to the inhibitory effects of MDPV. The release of monoamines through OCT3, a low‐affinity transporter, presumably explains the paradoxical synergistic effects of inhibitors and substrates (Mayer et al., 2019). [...] Another feature that distinguishes [synthetic cathinones (SCs)] from amphetamines is their negligible interaction with the trace amine associated receptor 1 (TAAR1). Activation of this receptor reduces the activity of dopaminergic neurones, thereby reducing psychostimulatory effects and addictive potential (Miller, 2011; Simmler et al., 2016). Amphetamines are potent agonists of this receptor, making them likely to self‐inhibit their stimulating effects. In contrast, SCs show negligible activity towards TAAR1 (Kolaczynska et al., 2021; Rickli et al., 2015; Simmler et al., 2014, 2016). [...] It is worth noting, however, that for TAAR1 there is considerable species variability in its interaction with ligands, and it is possible that the in vitro activity of [rodent TAAR1 agonists] may not translate into activity in the human body (Simmler et al., 2016). The lack of self‐regulation by TAAR1 may partly explain the higher addictive potential of SCs compared to amphetamines (Miller, 2011; Simmler et al., 2013).". 
  27. ↑ 27.0 27.1 27.2 "Interaction of amphetamines and related compounds at the vesicular monoamine transporter". J Pharmacol Exp Ther 319 (1): 237–246. October 2006. doi:10.1124/jpet.106.103622. PMID 16835371. "A number of test drugs displayed no activity in the [3H]dopamine uptake inhibition assay (Table 1). For example, (+)- phenmetrazine and (–)-phenmetrazine, the major metabolites of phendimetrazine (Rothman et al., 2002), were essentially inactive. [...] In contrast, other amphetamine-type agents, such as phentermine, phenmetrazine, and 1-benzylpiperazine, are potent releasers of neuronal dopamine (Baumann et al., 2000, 2005; Rothman et al., 2002), but they are inactive at VMAT2. Agents such as these may prove to be valuable control compounds for determining the importance of vesicular release for the in vivo actions of amphetamine-type agents.". 
  28. ↑ 28.0 28.1 28.2 28.3 "Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy". J Psychopharmacol 35 (5): 512–536. May 2021. doi:10.1177/0269881120920420. PMID 32909493. 
  29. ↑ 29.0 29.1 "The profile of mephedrone on human monoamine transporters differs from 3,4-methylenedioxymethamphetamine primarily by lower potency at the vesicular monoamine transporter". Eur J Pharmacol 755: 119–126. May 2015. doi:10.1016/j.ejphar.2015.03.004. PMID 25771452. 
  30. ↑ "Inhibition of plasma membrane monoamine transporters by beta-ketoamphetamines". Eur J Pharmacol 381 (1): 63–69. September 1999. doi:10.1016/s0014-2999(99)00538-5. PMID 10528135. 
  31. ↑ "Vesicular monoamine transporters: structure-function, pharmacology, and medicinal chemistry". Med Res Rev 31 (4): 483–519. July 2011. doi:10.1002/med.20187. PMID 20135628. 
  32. ↑ Simmler, Linda D. (2018). "Monoamine Transporter and Receptor Interaction Profiles of Synthetic Cathinones". Synthetic Cathinones. Current Topics in Neurotoxicity. 12. Cham: Springer International Publishing. pp. 97–115. doi:10.1007/978-3-319-78707-7_6. ISBN 978-3-319-78706-0. "While the determination of drug effects at the isolated target (i.e., DAT, NET, and SERT) can characterize the direct drug action at the target protein, other physiological components can also contribute significantly to the overall effect of the drug. It has been proposed that transporter-mediated, drug-induced efflux of neurotransmitter occurs through effects on the vesicular monoamine transporter 2 (VMAT2), depleting neurotransmitter from the vesicles into the cytosol (Nickell et al. 2014). Accordingly, full assessment of release would require testing the effects of a drug on the membrane transporters (SERT, DAT, and NET) and the effects of a drug at VMAT2. Alternatively, a more physiological system, such as synaptosomes or brain slices, could be used. However, reverse transport can also occur in cell lines that only express the plasma membrane transporters but not VMAT2 (Eshleman et al. 2013; Scholze et al. 2000) and in synaptosomes when VMAT2 is inhibited (Rothman et al. 2001)." 
  33. ↑ 33.0 33.1 33.2 33.3 33.4 33.5 33.6 "2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α2-adrenergic receptors". Psychopharmacology (Berl) 236 (3): 989–999. March 2019. doi:10.1007/s00213-019-05207-1. PMID 30904940. "In contrast to assay systems involving non-neuronal cells transfected with transporter proteins, synaptosomes possess all of the cellular machinery necessary for neurotransmitter synthesis, release, metabolism, and reuptake. Synaptosomes, however, do not model all of the effects of amphetamine-type agents because the use of reserpine removes any contribution of the vesicular monoamine transporter VMAT2 (SLC18A2) to the release process. In addition to acting as a substrate for plasma membrane monoamine transporters, amphetamine also binds to VMAT, resulting in the redistribution of monoamines from vesicular stores to the cytoplasm (Sulzer et al. 1995; Partilla et al. 2006; Freyberg et al. 2016). Although transporter substrates can induce monoamine release in the absence of VMAT binding (Fon et al. 1997), it is important to recognize that 2-aminoindans may have effects in intact nerve terminals that are not fully replicated in synaptosomes. Follow-up studies will be conducted to evaluate whether 2-aminoindans are capable of interacting with VMAT.". 
  34. ↑ 34.0 34.1 34.2 "Striatal dopamine neurotransmission: regulation of release and uptake". Basal Ganglia 6 (3): 123–148. August 2016. doi:10.1016/j.baga.2016.02.001. PMID 27141430. "2.2.1. DAT regulation by psychostimulants [...] Considerable evidence supports a role for DAT substrates, like amphetamine, in inducing DAT internalization in vivo and in vitro, thus decreasing DA uptake [390–395]. [...] While several kinases are involved in the regulation of DAT, PKC is by far the most thoroughly investigated [388,403]. PKC activation induces DAT internalization [393,404–406] although the mechanism of PKC activation by DAT substrates remains largely unknown [388,389,403,407,408]". 
  35. ↑ 35.0 35.1 35.2 35.3 35.4 35.5 35.6 "Pharmacology of Drugs Used as Stimulants". J Clin Pharmacol 61 Suppl 2: S53–S69. August 2021. doi:10.1002/jcph.1918. PMID 34396557. "Release by an indirect agonist is termed reverse transport and may require buildup of neurotransmitter in the nerve cytoplasm [...] Stimulants can act to stimulate presynaptic (CNS) or prejunctional (periphery) receptors for the neurotransmitter on nerve terminals to control release from those endings. These receptors are usually inhibitory and are marked as I (either NE, DA, or 5-HT inhibitory receptor) in Figure 1 and as α2 (inhibitory α2- adrenoceptor) in Figure 2, respectively. For instance, α2-adrenoceptors are present as autoreceptors on noradrenergic nerves and mediate an inhibition of NE release both in the periphery and CNS (see Figures 1 and 2).71 [...] Stimulants can act to stimulate, either directly or indirectly via increased release of the monoamine neurotransmitter, receptors for the neurotransmitter on nerves or effector cells situated postsynaptically/postjunctionally to the monoaminergic neuron. [...] Receptor-mediated actions of amphetamine and other amphetamine derivatives [...] may involve trace amine-associated receptors (TAARs) at which amphetamine and MDMA also have significant potency.85–87 Many stimulants have potency at the rat TAAR1 in the micromolar range but tend to be about 5 to 10 times less potent at the human TAAR1, [...] Activation of the TAAR1 receptor causes inhibition of dopaminergic transmission in the mesocorticolimbic system, and TAAR1 agonists attenuated psychostimulant abuse-related behaviors.89 It is likely that TAARs contribute to the actions of specific stimulants to modulate dopaminergic, serotonergic, and glutamate signaling,90 and drugs acting on the TAAR1 may have therapeutic potential.91 In the periphery, stimulants such as MDMA and cathinone produce vasoconstriction, part of which may involve TAARs, although only relatively high concentrations produced vascular contractions resistant to a cocktail of monoamine antagonist drugs.86". 
  36. ↑ 36.0 36.1 36.2 36.3 36.4 Vaughan, Roxanne A.; Henry, L. Keith; Foster, James D.; Brown, Christopher R. (2024). "Post-translational mechanisms in psychostimulant-induced neurotransmitter efflux". Advances in Pharmacology. 99. Elsevier. pp. 1–33. doi:10.1016/bs.apha.2023.10.003. ISBN 978-0-443-21933-7. https://books.google.com/books?id=2Sr6EAAAQBAJ&pg=PA1. "The characteristics and mechanisms of efflux are complex and incompletely understood, and have been summarized in many comprehensive reviews including (Reith & Gnegy, 2020; Robertson, Matthies, & Galli, 2009; Sitte & Freissmuth, 2015). [...] Early studies implicating protein phosphorylation in AMPH-evoked DA efflux were performed by Giambalvo, who demonstrated that DAT-mediated uptake of AMPH impacted the activity and subcellular localization of protein kinase C (PKC) with characteristics that correlated with DA efflux (Giambalvo, 1992), and Gnegy and colleagues, whose many studies reinforced the relationship between efflux, kinases, and ionic conditions including PKC, PKCβ, Ca2+, and Ca1+-calmodulin regulated protein kinase (CaMK) (Gnegy et al., 2004; Johnson, Guptaroy, Lund, Shamban, & Gnegy, 2005; Kantor, Hewlett, & Gnegy, 1999). [...] With respect to DAT most studies have focused on PKC, CaMK, and mitogen activated protein kinases (MAPKs), but many other signaling and kinase pathways have been implicated in efflux mechanisms for all of the MATs (Bermingham & Blakely, 2016; Vaughan & Foster, 2013). [...] DAT phosphorylation stimulated by AMPH or METH also occurs on this domain and is blocked by PKC inhibitors (Cervinski et al., 2005; Karam et al., 2017), indicating the capacity of the drugs to involve the PKC pathway. How this occurs is not known, but could potentially follow from drug perturbation of local ion/Ca2+ concentrations that impact PTM enzymes, or alternatively could occur by substrate-driven induction of transporter conformations in which phosphorylation sites become more or less available to enzyme action. [...] There are many other Ser and Thr residues on DAT intracellular loops and domains that may serve as phosphorylation sites, and in vitro studies have demon- strated phosphorylation of N— and C—terminal peptide sequences by many kinases in addition to PKC, ERK, and CaMK that have been implicated in regulation and efflux including protein kinase A (PKA), protein kinase G (PKG), casein kinase 2 (CK2), p38 kinase, JNK2, Cdk5, and Akt1 (Gorentla I et al., 2009; Vaughan & Foster, 2013). [...] The regulatory, efflux, and post-translational characteristics of NET and SERT show many similarities to DAT that indicate conservation of mechanism, but also some distinct properties that reflect requirements of specific neuronal populations. [...] With respect to efflux there are many similarities between SERT, NET, and DAT that indicate conservation of mechanisms." 
  37. ↑ 37.0 37.1 37.2 "Regulation of the dopamine transporter: aspects relevant to psychostimulant drugs of abuse". Ann N Y Acad Sci 1187: 316–340. February 2010. doi:10.1111/j.1749-6632.2009.05148.x. PMID 20201860. "However, another significant question remains: how might amphetaminergic substrates activate PKC in the first place? PKC activity is regulated by Ca2+ and diacylglycerol, a phospholipid metabolite generated in concert with inositol triphosphate by the enzyme phospholipase C (PLC), which is also Ca2+ dependent. [...] Usually, PLC is activated by agonist binding at GPCRs coupled to the Gq/11- type α-subunit; however, compounds, such as amphetamine and methamphetamine, lack significant affinity for GPCRs other than the trace amine-associated receptor 1 (TAAR1), a Gs-coupled receptor.74 [...] Interestingly, inhibition of the Na+/Ca2+ antiporter with amiloride also blocked amphetamine-induced PKC activation, suggesting that the ionic effects of DAT substrate translocation can directly influence activation of intracellular signaling cascades. When substrates are transported across the plasma membrane via the DAT, sodium ions are cotransported, and this increase in intracellular sodium concentration may cause Na+/Ca2+ antiporters at mitochondrial and endoplasmic reticulum membranes to operate in reverse, favoring a net flux of Ca2+ into the cytosolic compartment. [...]". 
  38. ↑ "Amphetamine action at the cocaine- and antidepressant-sensitive serotonin transporter is modulated by αCaMKII". J Neurosci 35 (21): 8258–8271. May 2015. doi:10.1523/JNEUROSCI.4034-14.2015. PMID 26019340. "Amphetamine-induced transport reversal at the closely related dopamine transporter (DAT) has been shown previously to be contingent upon modulation by calmodulin kinase IIα (αCaMKII). Here, we show that not only DAT, but also SERT, is regulated by αCaMKII. Inhibition of αCaMKII activity markedly decreased amphetamine-triggered SERT-mediated substrate efflux in both cells coexpressing SERT and αCaMKII and brain tissue preparations. [...] Moreover, we found that genetic deletion of αCaMKII impaired the locomotor response of mice to [MDMA] and blunted d-fenfluramine-induced prolactin release, substantiating the importance of αCaMKII modulation for amphetamine action at SERT in vivo as well. SERT-mediated substrate uptake was neither affected by inhibition of nor genetic deficiency in αCaMKII.". 
  39. ↑ "Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters". Pharmacol Rev 68 (4): 888–953. October 2016. doi:10.1124/pr.115.012260. PMID 27591044. 
  40. ↑ "Amphetamine-induced reverse transport of dopamine does not require cytosolic Ca2". J Biol Chem 299 (8). August 2023. doi:10.1016/j.jbc.2023.105063. PMID 37468107. "[...] AMPH is a substrate of DAT and causes nonexocytotic efflux of DA by reversing the direction of transport via DAT through a yet not fully understood mechanism (4–7). To improve our insights into AMPH-induced efflux with a focus on the unsettled role of Ca2+, we establish here a novel approach enabling simultaneous assessment of DA efflux and intracellular signaling pathways by live fluorescent imaging of cultured DA midbrain neurons. [...] our data provide strong evidence that AMPH-induced DA efflux via DAT in DArgic neurons does not require Ca2+ but primarily relies on the concerted action of AMPH on VMAT2 and DAT. [...] [...] Summarized, we employ a live imaging approach enabling parallel monitoring of DA efflux and activation of intracellular signaling pathways in cultured DArgic neurons. Our data reveal in the neurons profound AMPH-induced DA efflux that strikingly neither requires Ca2+ signaling nor activation of the kinases PKC and CaMKIIα. However, the efflux depends on both the activity of VMAT2 and DAT, substantiating the unequivocal concerted importance of both transporters for the pharmacological action of AMPH on DArgic neurons. [...]". 
  41. ↑ 41.0 41.1 "Avenues for the development of therapeutics that target trace amine associated receptor 1 (TAAR1)". J Med Chem 55 (5): 1809–1814. March 2012. doi:10.1021/jm201437t. PMID 22214431. "Although a detailed and rigorous description of the regional distribution of TAAR1 protein and mRNA expression has yet to be accomplished, it is established that TAAR1 protein and mRNA are expressed in monoaminergic brain regions.3,16,26 In our laboratory, we exploited our prowess with assessing changes in kinetic activity of the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT) to assess TAAR1 functionality. Because many of the identified ligands that activate TAAR1 are also substrates at the monoamine transporters and TAAR1 localization in transfected cells was shown to remain largely intracellular,4 we had reasoned early on that monoamine transporters could serve as conduits for TAAR1 agonists to enter cells, thereby providing access of the agonist to an intracellular pool of TAAR1 receptors. We speculated that if this were the case there could be a special relationship between TAAR1 and monoamine transporters because they share some of the same ligands. Indeed, we observed substantially enhanced CRE-luciferase signaling in transfected cells that co-expressed both TAAR1 and a monoamine transporter (DAT, NET or SERT).9,16 Because monoamine transporter kinetic regulation and internalization is a consequence of upregulated cellular phosphorylation cascades,27,28,29 we reasoned that the enhanced TAAR1 signaling could in turn trigger changes in the kinetic activity of the monoamine transporters under conditions of co-localization. This too was born out in a series of studies from our laboratory which demonstrated that TAAR1 activation drives the PKA and PKC cellular signaling cascades that result in inhibition of monoamine uptake and transporter reversal (efflux) in DAT/TAAR1, NET/TAAR1 and SERT/TAAR1 co-transfected cells in vitro, as well as in mouse and primate striatal (DAT, SERT) and thalamic (NET) synaptosomes ex vivo.22,23,24,25,30 TAAR1 specificity for mediation of the observed kinetic effects on the monoamine transporters was further confirmed in these studies by demonstrating the absence of noncompetitive effects of the trace amine beta-phenylethylamine (β-PEA),23 the common biogenic amines,24 and methamphetamine25 on uptake inhibition and substrate-induced monoamine efflux in synaptosomes generated from TAAR1 knockout mice. Accordingly, specific drugs that target TAAR1 will likely result in alterations in monoamine kinetic function and brain monoamine levels via this mechanism.". 
  42. ↑ 42.0 42.1 42.2 42.3 42.4 42.5 "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". Journal of Neurochemistry 116 (2): 164–176. January 2011. doi:10.1111/j.1471-4159.2010.07109.x. PMID 21073468. "In a later study, Xie and Miller (2009a) resolved this issue by demonstrating that methamphetamine could induce [3 H]dopamine efflux in DAT cells or in TAAR1 knockout mouse striatal synaptosomes when the cells or synaptosomes were loaded with high concentrations of [ 3 H]dopamine (1 μM or higher), indicating that the direct effect of methamphetamine on the dopamine transporter to cause [3 H]dopamine efflux is dependent on the pre-loading concentration of [3 H]dopamine. But the efflux caused by methamphetamine under these conditions in DAT cells was not associated with either the PKA or the PKC phosphorylation pathways whereas it was blocked by methylphenidate. Further studies showed that TAAR1-mediated effects of methamphetamine on [3 H]dopamine efflux occurred at both lower and higher (1 μM) loading concentrations of [ 3 H]dopamine in TAAR1-DAT cells or in wild type mouse striatal synaptosomes, which could be blocked not only by methylphenidate but also by the PKC inhibitor Ro32-0432 (Xie and Miller 2009a). At the higher loading concentration, there was a greater amount of efflux observed in the presence of TAAR1 (in TAAR1-DAT cells or wild-type mouse striatal synaptosomes) than in its absence (in DAT cells or TAAR1 knockout mouse striatal synaptosomes), and it was only this relative greater amount of efflux that was sensitive to PKC inhibition. Accordingly, the TAAR1-mediated effects of methamphetamine on [3 H]dopamine efflux are dependent on PKC phosphorylation, whereas an observed TAAR1-independent, PKC-independent efflux occurs when cells or synaptosomes are loaded with high concentrations of [ 3 H]dopamine. [...] In a different mouse line, Lindemann et al. (2008) reported that TAAR1 knockout mice show an increased locomotive response to d-amphetamine after a single application of either 1 or 2.5 mg/kg. The increased locomotion correlated with a two- to threefold increase in extracellular dopamine, norepinephrine and serotonin levels in the TAAR1 knockout mice as compared with wild-type mice. [...] In further studies, electrophysiological analysis of dopaminergic neurons in the ventral tegmental area of TAAR1 knockout and wild-type mice revealed that the spontaneous firing rate of dopaminergic neurons was 8.6-fold higher in the TAAR1 knockout mice, and that activation of TAAR1 by 10 μM p-tyramine decreased the firing rate of dopaminergic neurons in wild type mice but not in TAAR1 knockout mice (Lindemann et al. 2008).". 
  43. ↑ 43.0 43.1 ""TAARgeting Addiction"--The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference". Drug Alcohol Depend 159: 9–16. February 2016. doi:10.1016/j.drugalcdep.2015.11.014. PMID 26644139. 
  44. ↑ 44.0 44.1 44.2 "Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction". Eur J Pharmacol 761: 345–352. August 2015. doi:10.1016/j.ejphar.2015.06.019. PMID 26092759. "In both wild-type and Taar 1-/- mice, amphetamine produced a robust increase in striatal release of DA, norepinephrine (NE), and serotonin (5-HT), but this effect was significantly greater in Taar 1-/- mice than in wild type mice (Lindemann et al., 2008; Wolinsky et al., 2007). These findings support the notion that TAAR 1 functionally operates as a negative modulator of monoaminergic neurotransmission. [...] amphetamine had no effect on the release of DA and NA in the NAc of Taar 1 Tg mice, which partially explains the finding that amphetamine-induced a weaker locomotor hyperactivity in Taar 1 Tg mice as compared to their wild type counterparts. [...] There are evidence that TAAR 1 can modulate DAT function in in vitro cell culture experiments. Xie et al reported that β-phenethylamine (β-PEA) inhibited uptake and induced efflux of monoamines in thalamic synaptosomes of rhesus monkeys and wild-type mice, but not in synaptosomes of Taar 1-/- mice. Furthermore, the effect of β-PEA on efflux was blocked by transporter inhibitors in either the transfected cells or wild-type mouse synaptosomes (Xie and Miller, 2008). They also found that methamphetamine inhibited DA uptake, enhanced dopamine efflux, and induced DAT internalization by acting as a TAAR 1 agonist (Xie and Miller, 2009). However, more recent studies show inconsistent results. Leo et al. found that the DA clearance was not changed in Taar 1-/- mice as compared to their wild type counterparts (Leo et al., 2014), suggesting that the DAT function remained intact. In addition, no significant changes of dopamine uptake were observed in slices from Taar 1-/- mice, suggesting that the effect of TAAR 1 activation on DA-related function is independent of DAT (Leo et al., 2014). These apparent discrepancies may be attributable to the assays and tissues used in the studies. Xie et al. used mouse and monkey cellular synaptosome preparations with tissues from putamen and thalamus (Xie and Miller, 2008) while Leo et al. used fast scan cyclic voltammetry to measure DA uptake in mouse striatal slices (Leo et al., 2014). [...] Taar 1-/- mice displayed a behavioral phenotype of supersensitivity to amphetamine and cocaine, as evidenced by drug-induced increases in both locomotor activity and rearing as compared with wild-type littermates (Lindemann et al., 2008; Wolinsky et al., 2007). In contrast, Taar Tg mice responded to amphetamine in an opposite manner and showed a reduced and delayed response to amphetamine as compared with wild-type mice, indicating that Taar Tg mice are hyposensitive to amphetamine (Revel et al., 2012a). Methamphetamine also produced similar behavioral outcome in Taar 1-/- mice (Achat-Mendes et al., 2012).". 
  45. ↑ Miner N (2019). The Modulatory Role of TAAR1 in Neurotoxicity of Substituted Amphetamines (Thesis). unav. pp. 33–34. doi:10.6083/qf85nb81p. A significant body of in vitro research has investigated TAAR1 modulation of DAT, primarily by the Miller laboratory. [...] Functionality of DAT is also modulated by TAAR1 as application of DA inhibited [3H]DA uptake and induced [3H]DA release in TAAR1/DAT cells compared to cells only expressing DAT (Xie and Miller, 2007; Xie et al., 2008b). [...] However, it has been argued the conduction of this research in vitro diminishes its validity. Administration of β-PEA or the TAAR1 agonist RO5166017 diminishes hyperlocomotion in DAT-KO mice, indicating activation of TAAR1 functions independently of DAT (Sotnikova et al., 2004; Revel et al., 2011). This theory is bolstered by FSCV experiments. Evoked DA release and uptake, measured by Tau and half-life, are the same between genotypes. DA overflow is greater in the NAc of Taar1-KO than -WT mice, attributed to increased basal DA levels, but DA uptake is still the same between genotypes (Leo et al., 2014). Similarly, the partial TAAR1 agonist RO5203648 diminishes cocaine-induced DA overflow in the NAc without altering DA uptake, also indicating a DAT-independent mechanism (Pei et al., 2014). Further research is needed to better elucidate the interaction between TAAR1 and DAT.
  46. ↑ 46.0 46.1 "Trace amine-associated receptor 1 (TAAR1) agonism as a new treatment strategy for schizophrenia and related disorders". Trends Neurosci 46 (1): 60–74. January 2023. doi:10.1016/j.tins.2022.10.010. PMID 36369028. "A study using the TAAR1-specific antagonist EPPTB showed that presynaptic blockade of TAAR1 reversed its ability to inhibit the firing rate of VTA dopaminergic neurons, which it normally brings about by activating inwardly rectifying potassium channels [45,48]. An increase in firing rates upon blocking TAAR1 with EPPTB suggests that TAAR1 is either constitutively active or under constant tonic activation from endogenous agonists. [...] A presynaptic interaction between TAAR1 and DAT function has also been suggested because some groups found evidence in cell culture that TAAR1 agonists inhibit DAT function via TAAR1 and D2AR [49,50,65]. Others find, however, that the effects of TAAR1 agonists and antagonist are unaltered in Dat−/− knockout mice, and that dopamine reuptake is unaffected by application of TAAR1 (ant)agonists or in TAAR1-KO animals [46,47]. One hypothesis that could unite the apparently conflicting findings is that TAs exert an inhibitory effect directly on DAT; indeed, PEA administration induces transient hyperlocomotion in mice, similar to the behaviour observed in Dat−/− animals [30]. More recent work suggests that TAAR1 activation mediates internalisation of DAT through regulating RhoA activity [53].". 
  47. ↑ "The Role of Biogenic Amine Transporters in Trace Amine-Associated Receptor 1 Regulation of Methamphetamine-Induced Neurotoxicity". J Pharmacol Exp Ther 371 (1): 36–44. October 2019. doi:10.1124/jpet.119.258970. PMID 31320495. "Previous research on TAAR1 modulation of DAT function has produced equivocal findings. In vitro, MA inhibits [3H]DA uptake, and [3H]DA release is increased in striatal tissue from Taar1 WT compared with KO mice (Xie and Miller, 2009). Similar findings were described in cells cotransfected with TAAR1 and DAT, compared with cells transfected only with DAT, in which MA-induced [3H]DA uptake inhibition and release were increased (Xie and Miller, 2007, 2009). However, these findings indicate MA-induced impairment of DAT function is increased when TAAR1 is activated, as opposed to in vivo treatment with AMPH or MDMA, by which striatal extracellular DA levels are increased when TAAR1 is not activated (Wolinsky et al., 2007; Lindemann et al., 2008; Di Cara et al., 2011). We were unable to replicate the results of Xie and Miller (2009) under similar in vitro conditions (Fig. 3). There was no difference in IC50 values for [3H]DA uptake inhibition by MA between synaptosomes from Taar1 WT and KO mice. [...] our results do not support an earlier hypothesis that TAAR1 modulates DAT (Xie and Miller, 2007, 2009; Xie et al., 2008b), as there was no evidence of an interaction under conditions described above. Recent reports support our findings that the DAT is unaffected by TAAR1. Coadministration of MA and the TAAR1 partial agonist RO523648 did not alter [3H]DA uptake and release in striatal synaptosomes in rats (Cotter et al., 2015). Fast-scan cyclic voltammetry showed no difference in DA clearance, as mediated by DAT, in striatal tissue from Taar1 WT compared with KO mice (Leo et al., 2014). [...] Given the lack of interaction, DAT is an improbable mediator of TAAR1 regulation of MA-induced neurotoxicity. [...] activation of TAAR1 did not modulate in vitro MA-impairment of DAT function or DAT expression. As TAAR1 activation did not alter the function or expression of DAT in whole synaptosomes or VMAT2 located on membrane-associated vesicles, these results indicate TAAR1 does not interact with these transporters on the plasma membrane but does affect intracellular VMAT2 function.". 
  48. ↑ "Taar1-mediated modulation of presynaptic dopaminergic neurotransmission: role of D2 dopamine autoreceptors". Neuropharmacology 81: 283–291. June 2014. doi:10.1016/j.neuropharm.2014.02.007. PMID 24565640. "Importantly, we have documented that neither Tau nor the half-life of released DA are changed in slices from TAAR1-KO animals, indicating that TAAR1-KO mice exhibit unaltered DA uptake ability and thereby normal dopamine transporter (DAT) functionality. It is believed that Tau and the half-life of released DA are reliable measures for detecting changes in DA uptake because they are strongly correlated with changes in the Km of DAT mediated DA uptake (Yorgason et al., 2011). Thus, these neurochemical in vivo studies, as well as previous demonstrations of the functional activity of TAAR1 ligands in mice lacking the DAT (Sotnikova et al., 2004; Revel et al., 2012a), provide little support for the postulated role of TAAR1 in modulating DAT activity that is based mostly on in vitro cell culture experiments (Miller et al., 2005; Xie et al., 2008; Miller, 2011). [...] Notably, neither [the TAAR1 agonist (RO5166017) nor the TAAR1 antagonist (EPPTB)] changed the kinetics of DA uptake as evidenced by the Tau and DA half-life estimations, indicating that DAT-mediated function is not altered by the action of the drugs on TAAR1.". 
  49. ↑ 49.0 49.1 "Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA)". J Neurosci 31 (47): 16928–16940. November 2011. doi:10.1523/JNEUROSCI.2502-11.2011. PMID 22114263. 
  50. ↑ 50.0 50.1 50.2 "Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class". Bioorganic & Medicinal Chemistry 19 (23): 7044–7048. December 2011. doi:10.1016/j.bmc.2011.10.007. PMID 22037049. "While our data suggest a role for TAAR1 in eliciting amphetamine-like stimulant effects, it must be borne in mind that the observed in vivo effects are likely to result from interaction with both TAAR1 and monoamine transporters. Thus it has been shown that the selective TAAR1 agonist RO5166017 fully prevented psychostimulant-induced and persistent hyperdopaminergia-related hyperactivity in mice.42 This effect was found to be DAT-independent, since suppression of hyperactivity was observed in DAT-KO mice.42 The collected information leads us to conclude that TAAR1 is a stereoselective binding site for amphetamine and that TAAR1 activation by amphetamine and its congeners may contribute to the stimulant properties of this class of compounds. [...] it has been shown that β-PEA and methamphetamine effects in cells expressing TAAR-DAT significantly exceed those observed in cells expressing DAT only. Consistent with this conclusion is the higher potency of (S)-[amphetamine] in rat synaptosomes relative to cloned human DAT cells (EC50 60 nM vs 240 nM).". 
  51. ↑ 51.0 51.1 51.2 "Psychoactive Drugs-From Chemical Structure to Oxidative Stress Related to Dopaminergic Neurotransmission. A Review". Antioxidants 10 (3): 381. March 2021. doi:10.3390/antiox10030381. PMID 33806320. "The DAT vs SERT ratios of synthetic cathinones are presented in Table 1. [...] Table 1. In vitro dopamine and serotonin uptake transporter inhibition (IC50 values) and release data (EC50 values). [...] The DAT vs SERT ratios of amphetamine derivatives and cocaine are presented in Table 2. [...] Table 2. In vitro dopamine and serotonin uptake transporter inhibition (IC50 values) and release data (EC50 values). [...] * in vitro studies for neurotransmitter reuptake inhibition and release using HEK293 (Human Embryonic Kidney 293) cell line expressing DAT and SERT (IC50 and EC50 values are expressed in μM). [(Note: HEK293 cells lack TAAR1 expression: "HEK-293 cells do not express TAAR1 (Reese et al., 2007; Xie and Miller, 2007)" (Small et al., 2023 [doi:10.1124/jpet.122.001573]).)]". 
  52. ↑ 52.0 52.1 52.2 "Trace Amines and Their Receptors". Pharmacol Rev 70 (3): 549–620. July 2018. doi:10.1124/pr.117.015305. PMID 29941461. 
  53. ↑ 53.0 53.1 53.2 "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1". J Pharmacol Exp Ther 357 (1): 134–144. April 2016. doi:10.1124/jpet.115.229765. PMID 26791601. https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA. 
  54. ↑ "Trace amine-associated receptor 1-Family archetype or iconoclast?". Pharmacol Ther 116 (3): 355–390. December 2007. doi:10.1016/j.pharmthera.2007.06.007. PMID 17888514. "[AMPH and METH] promote DA release from synaptic storage vesicles into the cytoplasm (Partilla et al., 2006) and then into the extracellular space via DAT with an EC50 of 25 nM and a Ki uptake in rat synaptosomes of 34 nM (Rothman et al., 2001). These are drug concentrations approximately 20-30 fold lower than the EC50 values Reese et al. (2007) calculated for eliciting an in vitro functional response from rTAAR1 (0.8 μM). However, experienced METH users can typically consume gram quantities of drug per day (Kramer et al., 1967) and achieve peak blood concentrations of 100 μM (Derlet et al., 1989; Baselt, 2002; Peters et al., 2003). [...] The extracellular free concentration of METH surrounding relevant human dopaminergic synapses in the brain presumably is the relevant pharmacodynamic parameter, at least in part, underlying the desirable effects of the drug. Although this value is not known with certainty for humans METH serum levels typically represent one tenth of what is found in rat brain (Riviere et al., 2000). Consequently, when considered together with the human forensic evidence the in vitro results of Reese et al. (2007) are consistent with the interpretation that in vivo the human TAAR1 is likely to be a mediator of at least some of METH's effects.". 
  55. ↑ "Trace amine-associated receptor 1 displays species-dependent stereoselectivity for isomers of methamphetamine, amphetamine, and para-hydroxyamphetamine". J Pharmacol Exp Ther 321 (1): 178–186. April 2007. doi:10.1124/jpet.106.115402. PMID 17218486. "The EC50 of (+)-AMPH to release DA via DAT is 25 nM, with Ki uptake values in rat synaptosomes for this neurotransmitter of 34 nM at the DAT, concentrations approximately 20- to 30-fold lower than the EC50 values we calculated for eliciting an in vitro functional response from rTAAR1 (0.8 μM). Chronic METH abusers can typically consume gram quantities of drug per day (Kramer et al., 1967). [...] plasma concentrations of both drugs can reach into the high-micromolar range (Drummer and Odell, 2001; Baselt, 2002; Peters et al., 2003). Although the extracellular free concentration of METH around relevant human dopaminergic synapses presumably involved in producing desirable CNS effects is not known with certainty, in rats METH serum levels are typically 1/10 what is found in brain (Riviere et al., 2000). Forensic evidence indicates that experienced METH users can typically achieve peak blood concentrations of 100 μM (Baselt, 2002; Peters et al., 2003). Both isomers of METH were full agonists of h-rChTAAR1 over a range of EC50 values from 3.5 to ~15 μM, concentrations often exceeded in the blood of human METH addicts (Derlet et al., 1989). If TAAR1s, whether expressed in the CNS or periphery, are exposed to such concentrations, it is possible they could become functionally activated. [...] Given that the EC50 values for METH and AMPH activation of the h-rChTAAR1 in vitro are well below the concentrations frequently found in addicts, we suggest that TAAR1 might be a potential mediator of some of the effects of AMPH and METH in humans, including hyperthermia and stroke.". 
  56. ↑ 56.0 56.1 "Neuronal Functions and Emerging Pharmacology of TAAR1". Taste and Smell. Topics in Medicinal Chemistry. 23. Cham: Springer International Publishing. 2014. pp. 175–194. doi:10.1007/7355_2014_78. ISBN 978-3-319-48925-4. "Interestingly, the concentrations of amphetamine found to be necessary to activate TAAR1 are in line with what was found in drug abusers [3, 51, 52]. Thus, it is likely that some of the effects produced by amphetamines could be mediated by TAAR1. Indeed, in a study in mice, MDMA effects were found to be mediated in part by TAAR1, in a sense that MDMA auto-inhibits its neurochemical and functional actions [46]. Based on this and other studies (see other section), it has been suggested that TAAR1 could play a role in reward mechanisms and that amphetamine activity on TAAR1 counteracts their known behavioral and neurochemical effects mediated via dopamine neurotransmission." 
  57. ↑ ""TAARgeting Addiction"--The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference". Drug Alcohol Depend 159: 9–16. February 2016. doi:10.1016/j.drugalcdep.2015.11.014. PMID 26644139. "That TAAR1 signaling is coupled to the inhibition of VTA DA neuron firing was a surprising finding. [...] earlier data suggested that TAAR1 activation leads to inhibition of DA uptake by DAT, promotion of DA efflux by DAT and DAT internalization which presumably would augment extracellular DA levels, whereas inhibition of DA neuronal firing rate would likely decrease extracellular DA levels, [...] this mismatch in expectations immediately attracted the attention of those trying to determine whether TAAR1 is a METH/AMPH and DA receptor in vivo as it is in vitro (Bunzow et al., 2001; Wainscott et al., 2007; Xie and Miller, 2009; Panas et al., 2012).". 
  58. ↑ 58.0 58.1 58.2 "Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine". ACS Chem Neurosci 9 (10): 2408–2427. October 2018. doi:10.1021/acschemneuro.8b00155. PMID 30001118. PMC 6197894. https://shaunlacob.com/wp-content/uploads/2020/12/DC-MDMA.pdf. "[...] it is unclear if TAAR1 plays any role in the effects of MDMA in humans, as MDMA does not activate human TAAR1 in cellular assays like it does mouse and rat TAAR1.84". 
  59. ↑ "TAAR1 and Psychostimulant Addiction". Cellular and Molecular Neurobiology 40 (2): 229–238. March 2020. doi:10.1007/s10571-020-00792-8. PMID 31974906. "Beside the TAAR1-KO mice, animals that overexpress taar1 in the brain were also generated, which was named as taar1 Tg mice (Revel et al. 2012a). Before discussing the behaviors of this line of taar1 Tg mice, it should be kept in mind that taar1 was expressed in all types of neurons in the whole brain of this mice strain, which is in contrast with the specifc expression pattern of that in the wildtype animals (Revel et al. 2012a). The electrophysiological results showed that excitatory and inhibitory inputs into the VTA were altered in the taar1 Tg mice (Revel et al. 2012a). Interestingly, although the basal levels of dopamine and norepinephrine in the nucleus accumbens (NAc) were elevated, amphetamine did not alter dopamine levels in the taar1 Tg mice (Revel et al. 2012a). Consistently, behavioral test showed that AMPH led to hyperactivity in WT but not in taar1 Tg mice (Revel et al. 2012a).". 
  60. ↑ 60.0 60.1 60.2 60.3 60.4 60.5 "The Alkylamine Stimulant 1,3-Dimethylamylamine Exhibits Substrate-Like Regulation of Dopamine Transporter Function and Localization". J Pharmacol Exp Ther 386 (2): 266–273. August 2023. doi:10.1124/jpet.122.001573. PMID 37348963. "[...] a proposed intracellular target for amphetamine is the [TAAR1], a [GPCR] that is expressed on intracellular membranes in DA neurons (Miller, 2011). Phenethylamine stimulants have been proposed to activate TAAR1, leading to increased cAMP generation and RhoA activation, with subsequent enhancement of DAT reverse transport and endocytosis (Xie and Miller, 2007, 2008, 2009; Underhill et al., 2021). Methamphetamine-induced DAT endocytosis was found to be dependent on TAAR1 expression and PKA activity as suggested by use of the kinase inhibitor H89 (Xie and Miller, 2009). However, evidence indicating that amphetamine-induced endocytosis is independent of TAAR1 includes 1) HEK-293 cells do not express TAAR1 (Reese et al., 2007; Xie and Miller, 2007) but do exhibit amphetamine-induced DAT endocytosis [present studies and (Saunders et al., 2014; Cheng et al., 2015; Wheeler et al., 2015)]; 2) cAMP and PKA activation, which are stimulated by TAAR1, antagonized amphetamine-induced DAT endocytosis in heterologous cells and DA neurons [present studies and (Wheeler et al., 2015)]; and 3) in cell lines and rodent striatal synaptosomes, PKA activation increased DAT Vmax, consistent with increased plasma membrane expression (Pristupa et al., 1998; Page et al., 2004; Batchelor and Schenk, 2018). Additionally, DMAA induced DAT endocytosis (Figs. 3 and 4) despite exhibiting no activity at human TAAR1 in receptor binding studies (Rickli et al., 2019). Therefore, although some evidence does support a role of TAAR1 in modulating amphetamine-induced DAT endocytosis, the present studies suggest that DMAA and amphetamine promote DAT endocytosis through a TAAR1-independent mechanism.". 
  61. ↑ "TAAR Agonists". Cell Mol Neurobiol 40 (2): 257–272. March 2020. doi:10.1007/s10571-019-00774-5. PMID 31848873. "Amphetamine might act on TAAR1 to activate Gαs pathway and phosphorylate monoamine transporter such as dopamine transporter (DAT), leading to its internalization and ceased transport (Bunzow et al. 2001; Miller 2011). Behaviorally, knockout of TAAR1 in mice leads to locomotor supersensitivity induced by amphetamine, although the connection to regulation of monoamine system is undetermined and needs further investigation (Achat-Mendes et al. 2012; Lindemann et al. 2008).". 
  62. ↑ Reese EA (2008). Trace amine-associated receptor 1: a novel target of methamphetamine (Thesis). doi:10.6083/M4ZK5DNR. In a recent study it was reported that AMPH induced locomotor function of TAAR1 knockout mice was increased compared to the response of wild type mice (Lindemann et al., 2007). In addition, they reported a 2½ fold increase in dopamine, noradrenaline, and serotonin release, in response to AMPH, in TAAR1 knockout mice compared to wild type mice. These results are similar to the increase in DA and NE release reported in a study of another TAAR1 KO mouse (Wolinsky et al., 2007). These findings of increased DA release and increased locomoter effects in the TAAR1 KO are reconciled with the proposed model as follows. The increased DA release of the TAAR1 KO may be due to reduced DAT internalization. With more DAT (or NET or SERT) remaining at the cell surface, more neurotransmitters can be reverse exchanged upon application of AMPH. The increased DA release would also explain the increased locomotor activity of the KO vs WT. The WT TAAR1 cells would undergo DAT internalization as described in the model. With fewer surface transporters, less DA would be reverse exchanged resulting in less DA release compared to levels in the KO mice.
  63. ↑ "Potential of Ligands for Trace Amine-Associated Receptor 1 (TAAR1) in the Management of Substance Use Disorders". CNS Drugs 35 (12): 1239–1248. December 2021. doi:10.1007/s40263-021-00871-4. PMID 34766253. "Moreover, while deletion of TAAR1 led to increased frequency of spontaneous firing frequency of serotonin neurons in brain slices [36], TAAR1 full agonists significantly inhibited the firing frequency in DRN serotonin neurons [28, 38]. [...] In vitro electrophysiological recordings showed a remarkable increase in the spontaneous firing rate of dopamine neurons in the VTA of TAAR1-KO mice [36]. While the endogenous TAAR1 agonist TYR decreased the firing rate of dopamine neurons in slices from WT mice, it had no effect in slices from TAAR1-KO mice [36]. [...] Similar to TYR, [the TAAR1 full agonist] RO5166017 reduced the firing rate of VTA dopamine neurons and DRN serotonin neurons in brain slices from WT but not TAAR1-KO mice, through the activation of K+-mediated outward current, which can be blocked by TAAR1 antagonist EPPTB [38]. [...] [The TAAR1 full agonist] RO5256390 decreased the firing frequency of VTA dopamine and DRN serotonin neurons in brain slices from WT but not TAAR1-KO mice, [...]". 
  64. ↑ "Pharmacological characterization of designer cathinones in vitro". Br J Pharmacol 168 (2): 458–470. January 2013. doi:10.1111/j.1476-5381.2012.02145.x. PMID 22897747. "β-Keto-analogue cathinones also exhibited approximately 10-fold lower affinity for the TA1 receptor compared with their respective non-β-keto amphetamines. [...] Activation of TA1 receptors negatively modulates dopaminergic neurotransmission. Importantly, methamphetamine decreased DAT surface expression via a TA1 receptor-mediated mechanism and thereby reduced the presence of its own pharmacological target (Xie and Miller, 2009). MDMA and amphetamine have been shown to produce enhanced DA and 5-HT release and locomotor activity in TA1 receptor knockout mice compared with wild-type mice (Lindemann et al., 2008; Di Cara et al., 2011). Because methamphetamine and MDMA auto-inhibit their neurochemical and functional effects via TA1 receptors, low affinity for these receptors may result in stronger effects on monoamine systems by cathinones compared with the classic amphetamines.". 
  65. ↑ 65.0 65.1 65.2 "Amphetamine paradoxically augments exocytotic dopamine release and phasic dopamine signals". J Neurosci 33 (2): 452–463. January 2013. doi:10.1523/JNEUROSCI.2136-12.2013. PMID 23303926. "Drugs of abuse hijack brain-reward circuitry during the addiction process by augmenting action potential-dependent phasic dopamine release events associated with learning and goal-directed behavior. One prominent exception to this notion would appear to be amphetamine (AMPH) and related analogs, which are proposed instead to disrupt normal patterns of dopamine neurotransmission by depleting vesicular stores and promoting nonexocytotic dopamine efflux via reverse transport. This mechanism of AMPH action, though, is inconsistent with its therapeutic effects and addictive properties, which are thought to be reliant on phasic dopamine signaling. [...] These findings identify upregulation of exocytotic dopamine release as a key AMPH action in behaving animals and support a unified mechanism of abused drugs to activate phasic dopamine signaling. [...] Our results also raise the possibility that enhanced phasic dopamine signaling may underlie important clinical effects of AMPH. Modest activation of dopamine transients at the relatively low dose of 1 mg/kg used here may be an important action of medications that combine amphetamine salts (e.g., Adderall) used clinically (Joyce et al., 2007). Indeed, low doses of AMPH preserve and improve learning and behavioral performance (Mayorga et al., 2000; Wyvell and Berridge, 2000; Taylor and Jentsch, 2001; Zhang et al., 2003; Knutson et al., 2004). In contrast, high doses of AMPH can produce a behavioral profile similar to the positive symptoms associated with schizophrenia (Featherstone et al., 2007; Lisman et al., 2008). [...] Thus, disrupting the tight temporal concurrence between dopamine transients and important external cues due to hyperactive phasic dopamine signaling may contribute to AMPH-induced psychosis (Featherstone et al., 2007).". 
  66. ↑ 66.0 66.1 66.2 "Amphetamine elicits opposing actions on readily releasable and reserve pools for dopamine". PLOS ONE 8 (5). 2013. doi:10.1371/journal.pone.0060763. PMID 23671560. Bibcode: 2013PLoSO...860763C. "While there is little debate that behavioral effects of this important psychostimulant are associated with a hyperdopamine state [3–6], the underlying mechanisms by which this condition manifests have been the subject of intense study. Two, what ostensibly appear to be mutually exclusive, views have emerged. On the one hand, AMPH enhances tonic dopamine signaling by reversing dopamine transporter (DAT) direction, leading to a non-exocytotic, action potential-independent type of release or efflux that is driven by vesicular depletion and the redistribution of dopamine to the cytosol [7,8]. On the other hand, AMPH enhances phasic dopamine signaling by promoting burst firing of dopamine neurons [9,10], inhibiting dopamine uptake [11,12], and upregulating vesicular dopamine release [13,14]. How AMPH concurrently activates tonic and phasic dopamine signaling, the two fundamental modes of communication used by dopamine neurons [15], yet elicits opposing actions on vesicular dopamine stores is perplexing and unresolved.". 
  67. ↑ "The sigma-1 receptor as a regulator of dopamine neurotransmission: A potential therapeutic target for methamphetamine addiction". Pharmacol Ther 186: 152–167. June 2018. doi:10.1016/j.pharmthera.2018.01.009. PMID 29360540. 
  68. ↑ "The sigma-1 receptor modulates methamphetamine dysregulation of dopamine neurotransmission". Nat Commun 8 (1). December 2017. doi:10.1038/s41467-017-02087-x. PMID 29263318. Bibcode: 2017NatCo...8.2228S. "We found that σ1R activation prevents methamphetamine-induced, DAT-mediated increases in firing activity of dopamine neurons. In vitro and in vivo amperometric measurements revealed that σ1R activation decreases methamphetamine-stimulated dopamine efflux without affecting basal dopamine neurotransmission. Consistent with these findings, σ1R activation decreases methamphetamine-induced locomotion, motivated behavior, and enhancement of brain reward function. Notably, we revealed that the σ1R interacts with DAT at or near the plasma membrane and decreases methamphetamine-induced Ca2+ signaling, providing potential mechanisms.". 
  69. ↑ 69.0 69.1 Lam, Vincent (2017). Identification and in vivo Characterization of a Potential TAAR1 Antagonist. https://utoronto.scholaris.ca/items/663220b8-e229-44b8-9447-8250c75c9d7a. Retrieved 13 February 2025. "While no in vivo studies have been done with selective sigma 2 receptor ligands measuring amphetamine-mediated locomotor activity, it was found that sigma 2 receptor agonists potentiate amphetamine-mediated dopamine efflux in PC12 cells in vitro (Izenwasser et al., 1998; Weatherspoon and Werling, 1999). These in vitro results indicate that sigma 2 receptor agonists would potentiate amphetamine-, and potentially cocaine-mediated locomotor activity in vivo. Due to the lack of selective sigma 2 ligands, the precise mechanism of sigma 2 enhancement of dopamine release is not known. However, it has been postulated that sigma 2 activation leads to an increase in intracellular calcium, either through an interaction with the plasma membrane bound L-type calcium channels, or via the ER-bound IP3 ligand gated calcium channels (Zhang and Cuevas, 2002; Cassano et al., 2006, 2009). This increase in intracellular calcium is hypothesized to promote the activation of PKC, and therefore the phosphorylation of DAT, leading to an increase in extracellular dopamine (Derbez et al., 2002).". 
  70. ↑ "Therapeutic Potential of 5-HT2C Receptor Agonists for Addictive Disorders". ACS Chem Neurosci 6 (7): 1071–1088. July 2015. doi:10.1021/acschemneuro.5b00025. PMID 25870913. "The sampling of extracellular fluids using in vivo microdialysis provides a direct way to study drug effects on synaptic efflux of a neurotransmitter. Comparisons of dexfenfluramine and fluoxetine using this technique have revealed a significant difference between the effects of reuptake inhibition and release on extracellular 5-HT levels.34−36 For example, Tao et al.35 compared the effects of fluoxetine and dexfenfluramine on extracellular 5-HT in the hypothalamus, with the latter increasing basal 5-HT 6−16-fold, compared to 3-fold following fluoxetine (Figure 1A). These differences in magnitude reflect differences in the way that fluoxetine and dexfenfluramine elevate 5-HT. The ability of SSRIs to increase extracellular 5- HT is dependent on neuronal activity (i.e., impulse dependent) and is subject to autoreceptor feedback inhibition. In contrast, (dex)fenfluramine increases extracellular 5-HT by disrupting vesicular storage and promoting nonexocytotic release that is independent of both of these regulatory factors.36 [...] Figure 1. Comparison between a 5-HT releaser (dexfenfluramine) and SSRI (fluoxetine) on (A) extracellular 5-HT release sampled from rat hypothalamus, [...]". 
  71. ↑ 71.0 71.1 71.2 71.3 "Targeted screening for biogenic amine transporters: potential applications for natural products". Life Sci 78 (5): 512–518. December 2005. doi:10.1016/j.lfs.2005.09.001. PMID 16202429. 
  72. ↑ 72.0 72.1 72.2 "Therapeutic and adverse actions of serotonin transporter substrates". Pharmacology & Therapeutics 95 (1): 73–88. July 2002. doi:10.1016/s0163-7258(02)00234-6. PMID 12163129. 
  73. ↑ 73.0 73.1 "Serotonin releasing agents. Neurochemical, therapeutic and adverse effects". Pharmacology, Biochemistry, and Behavior 71 (4): 825–836. April 2002. doi:10.1016/s0091-3057(01)00669-4. PMID 11888573. 
  74. ↑ "The SH rat model of ADHD has profoundly different catecholaminergic responses to amphetamine's enantiomers compared with Sprague-Dawleys". Neuroscience 2007, San Diego, CA, Nov 3-7, 2007. Society for Neuroscience. 2007. https://www.abstractsonline.com/pp8/#!/1820/presentation/12987. "Both d- and l-[amphetamine (AMP)] evoked rapid increases in extraneuronal concentrations of [noradrenaline (NA)] and [dopamine (DA)] that reached a maximum 30 or 60 min after administration. However, the [spontaneously hypertensive rats (SHRs)] were much more responsive to AMP's enantiomers than the [Sprague-Dawleys (SDs)]. Thus, 3 mg/kg d-AMP produced a peak increase in [prefrontal cortex (PFC)] NA of 649 ± 87% (p<0.001) in SHRs compared with 198 ± 39% (p<0.05) in SDs; the corresponding figures for [striatal (STR)] DA were 4898 ± 1912% (p<0.001) versus 1606 ± 391% (p<0.001). At 9 mg/kg, l-AMP maximally increased NA efflux by 1069 ± 105% (p<0.001) in SHRs compared with 157 ± 24% (p<0.01) in SDs; the DA figures were 3294 ± 691% (p<0.001) versus 459 ± 107% (p<0.001)." 
  75. ↑ "Bupropion, methylphenidate, and 3,4-methylenedioxypyrovalerone antagonize methamphetamine-induced efflux of dopamine according to their potencies as dopamine uptake inhibitors: implications for the treatment of methamphetamine dependence". BMC Res Notes 6. June 2013. doi:10.1186/1756-0500-6-220. PMID 23734766. 
  76. ↑ 76.00 76.01 76.02 76.03 76.04 76.05 76.06 76.07 76.08 76.09 76.10 76.11 76.12 76.13 76.14 "Studies of the biogenic amine transporters. 14. Identification of low-efficacy "partial" substrates for the biogenic amine transporters". The Journal of Pharmacology and Experimental Therapeutics 341 (1): 251–262. April 2012. doi:10.1124/jpet.111.188946. PMID 22271821. 
  77. ↑ 77.00 77.01 77.02 77.03 77.04 77.05 77.06 77.07 77.08 77.09 77.10 77.11 77.12 77.13 77.14 77.15 77.16 77.17 77.18 77.19 77.20 77.21 77.22 77.23 77.24 77.25 "Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes". Psychopharmacology 231 (21): 4135–4144. October 2014. doi:10.1007/s00213-014-3557-7. PMID 24800892. 
  78. ↑ 78.0 78.1 78.2 Cite error: Invalid <ref> tag; no text was provided for refs named US11440879B2
  79. ↑ 79.0 79.1 "The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors". PLOS ONE 6 (10). 2011. doi:10.1371/journal.pone.0025790. PMID 22043293. Bibcode: 2011PLoSO...625790S. 
  80. ↑ "ADHD: current and future therapeutics". Behavioral Neuroscience of Attention Deficit Hyperactivity Disorder and Its Treatment. Current Topics in Behavioral Neurosciences. 9. 2012. pp. 361–390. doi:10.1007/7854_2011_125. ISBN 978-3-642-24611-1. 
  81. ↑ "Prospects for new drugs to treat binge-eating disorder: Insights from psychopathology and neuropharmacology". J Psychopharmacol 36 (6): 680–703. June 2022. doi:10.1177/02698811211032475. PMID 34318734. 
  82. ↑ "In vivo characterization of locally applied dopamine uptake inhibitors by striatal microdialysis". Synapse 6 (1): 106–12. 1990. doi:10.1002/syn.890060113. PMID 1697988. 
  83. ↑ "Modafinil and its structural analogs as atypical dopamine uptake inhibitors and potential medications for psychostimulant use disorder". Current Opinion in Pharmacology 56: 13–21. February 2021. doi:10.1016/j.coph.2020.07.007. PMID 32927246. 
  84. ↑ 84.0 84.1 84.2 84.3 "Phenylethylamine and tyramine are mixed-acting sympathomimetic amines in the brain". Life Sciences 58 (23): 2101–2114. 1996. doi:10.1016/0024-3205(96)00204-4. PMID 8649195. 
  85. ↑ "Enhancer Regulation of Dopaminergic Neurochemical Transmission in the Striatum". International Journal of Molecular Sciences 23 (15): 8543. August 2022. doi:10.3390/ijms23158543. PMID 35955676. 
  86. ↑ "Striking Neurochemical and Behavioral Differences in the Mode of Action of Selegiline and Rasagiline". International Journal of Molecular Sciences 24 (17). August 2023. doi:10.3390/ijms241713334. PMID 37686140. 
  87. ↑ "Regulation by Trace Amine-Associated Receptor 1 (TAAR1) of Dopaminergic-GABAergic Interaction in the Striatum: Effects of the Enhancer Drug (-)BPAP". Neurochem Res 50 (2). February 2025. doi:10.1007/s11064-025-04337-7. PMID 39903411. 
  88. ↑ 88.00 88.01 88.02 88.03 88.04 88.05 88.06 88.07 88.08 88.09 88.10 88.11 88.12 88.13 88.14 88.15 88.16 88.17 88.18 88.19 88.20 88.21 88.22 "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". Synapse 39 (1): 32–41. January 2001. doi:10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3. PMID 11071707. 
  89. ↑ "Characterization of beta-phenylethylamine-induced monoamine release in rat nucleus accumbens: a microdialysis study". European Journal of Pharmacology 349 (2–3): 163–169. May 1998. doi:10.1016/s0014-2999(98)00191-5. PMID 9671094. 
  90. ↑ "3,4-Methylenedioxymethamphetamine, mephedrone, and β-phenylethylamine release dopamine from the cytoplasm by means of transporters and keep the concentration high and constant by blocking reuptake". European Journal of Pharmacology 837: 72–80. October 2018. doi:10.1016/j.ejphar.2018.08.037. PMID 30172789. 
  91. ↑ Pihkal: A Chemical Love Story. Biography/science. Transform Press. 1991. ISBN 978-0-9630096-0-9. https://books.google.com/books?id=O8AdHBGybpcC. Retrieved 18 August 2024. 
  92. ↑ Tihkal: The Continuation. Transform Press. 1997. ISBN 978-0-9630096-9-2. https://books.google.com/books?id=jl_ik66IumUC. Retrieved 18 August 2024. 
  93. ↑ 93.0 93.1 93.2 The Shulgin Index: Psychedelic Phenethylamines and Related Compounds. 1. Transform Press. 2011. ISBN 978-0-9630096-3-0. 
  94. ↑ 94.0 94.1 "Amphetamines signal through intracellular TAAR1 receptors coupled to Gα13 and GαS in discrete subcellular domains". Mol Psychiatry 26 (4): 1208–1223. April 2021. doi:10.1038/s41380-019-0469-2. PMID 31399635. "Although the precise physiological role of TAAR1/G13-mediated DAT internalization remains to be established, it is likely that this pathway evolved to regulate the actions of endogenous amines including β-PEA, tyramine, 3-methoxytyramine, and DA. DA is a TAAR1 agonist (Fig. 1c) and recently, it was shown that the sustained elevation of extracellular DA seen following burst firing appears to be a consequence of DAT internalization by a Rho-dependent mechanism [51]. These results provide the first evidence that dopamine itself can act as a TAAR1 agonist to trigger transporter internalization in vivo. TAAR1 signaling also has the potential to serve as a sensor of cytoplasmic DA and its metabolites. At high cytosolic concentrations, DA becomes neurotoxic due to the formation of reactive oxygen species and quinones that can cause damage to the neuron [52]. Under normal conditions, DA transported through the DAT from the extracellular space is rapidly repackaged into synaptic vesicles or enzymatically metabolized. However, if cytoplasmic DA concentrations saturate these mechanisms, the reduction in surface levels of DAT mediated by TAAR1/G13 signaling may provide an additional means for maintaining free cytosolic DA below toxic levels.". 
  95. ↑ "Protective actions of the vesicular monoamine transporter 2 (VMAT2) in monoaminergic neurons". Mol Neurobiol 39 (2): 149–170. April 2009. doi:10.1007/s12035-009-8059-y. PMID 19259829. 
  96. ↑ "Presynaptic regulation of dopamine release: Role of the DAT and VMAT2 transporters". Neurochem Int 122: 94–105. January 2019. doi:10.1016/j.neuint.2018.11.004. PMID 30465801. 
  97. ↑ "Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders". Pharmacol Ther 144 (3): 268–282. December 2014. doi:10.1016/j.pharmthera.2014.06.006. PMID 24945828. 
  98. ↑ "Neurotoxicology of Synthetic Cathinone Analogs". Neuropharmacology of New Psychoactive Substances (NPS). Current Topics in Behavioral Neurosciences. 32. 2017. pp. 209–230. doi:10.1007/7854_2016_21. ISBN 978-3-319-52442-9. "This flooding of the cytoplasm and synaptic space with the oxidatively labile DA is thought to be a critical first step in the neurotoxic cascade of the amphetamines [73]. These conditions of elevated concentrations of cytosolic monoamines could be further aggravated by inhibition of MAO [91]. Unlike amphetamines, mephedrone and methylone have little if any affinity for VMAT-2 [33]. Therefore, their lack of neurotoxicity could derive from an inability to promote the release of DA from storage vesicles into the cytoplasm." 
  99. ↑ 99.0 99.1 Kostrzewa, Richard M. (2022). "Survey of Selective Monoaminergic Neurotoxins Targeting Dopaminergic, Noradrenergic, and Serotoninergic Neurons". Handbook of Neurotoxicity. Cham: Springer International Publishing. pp. 159–198. doi:10.1007/978-3-031-15080-7_53. ISBN 978-3-031-15079-1. 
  100. ↑ 100.0 100.1 100.2 100.3 "Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms". Prog Neurobiol 155: 149–170. August 2017. doi:10.1016/j.pneurobio.2015.09.011. PMID 26455459. 
  101. ↑ 101.0 101.1 101.2 "Is Attention-Deficit/Hyperactivity Disorder a Risk Syndrome for Parkinson's Disease?". Harv Rev Psychiatry 29 (2): 142–158. 2021. doi:10.1097/HRP.0000000000000283. PMID 33560690. https://rxisk.org/wp-content/uploads/2022/05/Baumeister-Is_Attention_Deficit_Hyperactivity_Disorder_a_Risk.4-2-1.pdf. "It has been suggested that the association between PD and ADHD may be explained, in part, by toxic effects of these drugs on DA neurons.241 [...] An important question is whether amphetamines, as they are used clinically to treat ADHD, are toxic to DA neurons. In most of the animal and human studies cited above, stimulant exposure levels are high relative to clinical doses, and dosing regimens (as stimulants) rarely mimic the manner in which these drugs are used clinically. The study by Ricaurte and colleagues248 is an exception. In that study, baboons orally self-administered a racemic (3:1 d/l) amphetamine mixture twice daily in increasing doses ranging from 2.5 to 20 mg/day for four weeks. Plasma amphetamine concentrations, measured at one-week intervals, were comparable to those observed in children taking amphetamine for ADHD. Two to four weeks after cessation of amphetamine treatment, multiple markers of striatal DA function were decreased, including DA and DAT. In another group of animals (squirrel monkeys), d/l amphetamine blood concentration was titrated to clinically comparable levels for four weeks by administering varying doses of amphetamine by orogastric gavage. These animals also had decreased markers of striatal DA function assessed two weeks after cessation of amphetamine.". 
  102. ↑ "Psychostimulants and movement disorders". Front Neurol 6: 75. 2015. doi:10.3389/fneur.2015.00075. PMID 25941511. "Amphetamine treatment similar to that used for ADHD has been demonstrated to produce brain dopaminergic neurotoxicity in primates, causing the damage of dopaminergic nerve endings in the striatum that may also occur in other disorders with long-term amphetamine treatment (57).". 
  103. ↑ 103.0 103.1 "Update on amphetamine neurotoxicity and its relevance to the treatment of ADHD". J Atten Disord 11 (1): 8–16. July 2007. doi:10.1177/1087054706295605. PMID 17606768. 
  104. ↑ "Potential adverse effects of amphetamine treatment on brain and behavior: a review". Mol Psychiatry 14 (2): 123–142. February 2009. doi:10.1038/mp.2008.90. PMID 18698321. "Though the paradigm used by Ricaurte et al. 53 arguably still incorporates amphetamine exposure at a level above much clinical use,14,55 it raises important unanswered questions. Is there a threshold of amphetamine exposure above which persistent changes in the dopamine system are induced? [...]". 
  105. ↑ "Amphetamine treatment similar to that used in the treatment of adult attention-deficit/hyperactivity disorder damages dopaminergic nerve endings in the striatum of adult nonhuman primates". J Pharmacol Exp Ther 315 (1): 91–98. October 2005. doi:10.1124/jpet.105.087916. PMID 16014752. 
  106. ↑ "Clinical neuroscience of amphetamine-type stimulants: From basic science to treatment development". Prog Brain Res 223: 295–310. 2016. doi:10.1016/bs.pbr.2015.07.010. PMID 26806782. "Repeated exposure to moderate to high levels of methamphetamine has been related to neurotoxic effects on the dopaminergic and serotonergic systems, leading to potentially irreversible loss of nerve terminals and/or neuron cell bodies (Cho and Melega, 2002). Preclinical evidence suggests that d-amphetamine, even when administered at commonly prescribed therapeutic doses, also results in toxicity to brain dopaminergic axon terminals (Ricaurte et al., 2005).". 
  107. ↑ "Is the treatment with psychostimulants in children and adolescents with attention deficit hyperactivity disorder harmful for the dopaminergic system?". Atten Defic Hyperact Disord 5 (2): 71–81. June 2013. doi:10.1007/s12402-013-0105-y. PMID 23605387. 
  108. ↑ "Synthetic Aminoindanes: A Summary of Existing Knowledge". Front Psychiatry 8. 2017. doi:10.3389/fpsyt.2017.00236. PMID 29204127. 
  109. ↑ 109.00 109.01 109.02 109.03 109.04 109.05 109.06 109.07 109.08 109.09 109.10 109.11 109.12 109.13 109.14 109.15 109.16 109.17 109.18 109.19 109.20 "The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain". European Journal of Pharmacology 559 (2–3): 132–137. March 2007. doi:10.1016/j.ejphar.2006.11.075. PMID 17223101. 
  110. ↑ 110.0 110.1 110.2 110.3 110.4 110.5 "Ethylenedioxy homologs of N-methyl-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) and its corresponding cathinone analog methylenedioxymethcathinone: Interactions with transporters for serotonin, dopamine, and norepinephrine". Bioorg Med Chem 23 (17): 5574–5579. September 2015. doi:10.1016/j.bmc.2015.07.035. PMID 26233799. "The present findings with MDMA are consistent with our previous data [15,17] and those reported by Simmler et al. [4] and Eshleman et al. [23] who examined the effects of MDMA and related drugs in human embryonic kidney (HEK) cells transfected with human SERT, DAT and NET. Thus, the molecular mechanism of action for MDMA at monoamine transporters is similar in rats and humans. On the other hand, the potency of (±)MDMA for releasing monoamines in rat brain synaptosomes shown here (i.e., 60–70 nM) is greater than its potency in transfected HEK cells (i.e., 1–20 μM). Such discrepancies in absolute potency could be related to species differences in drug responsiveness, differences in release assay methods employed, or the absence of important neuronal membrane proteins in non-neuronal HEK cells.". 
  111. ↑ "Studies of dioxole ring substituted 3,4-methylenedioxyamphetamine (MDA) analogues". Pharmacol Biochem Behav 34 (3): 571–576. November 1989. doi:10.1016/0091-3057(89)90560-1. PMID 2623014. 
  112. ↑ "Medicinal Chemistry and Structure–Activity Relationships". Amphetamine and Its Analogs: Psychopharmacology, Toxicology, and Abuse. Academic Press. 1994. pp. 3–41. ISBN 978-0-12-173375-9. https://www.researchgate.net/publication/265353973. 
  113. ↑ 113.0 113.1 113.2 113.3 113.4 113.5 113.6 "The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3,4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats". Psychopharmacology (Berl) 237 (12): 3703–3714. December 2020. doi:10.1007/s00213-020-05648-z. PMID 32875347. 
  114. ↑ 114.0 114.1 "Novel psychoactive benzofurans strongly increase extracellular serotonin level in mouse corpus striatum". J Toxicol Sci 41 (3): 329–337. 2016. doi:10.2131/jts.41.329. PMID 27193726. 
  115. ↑ 115.0 115.1 115.2 "Synthesis and pharmacological examination of benzofuran, indan, and tetralin analogues of 3,4-(methylenedioxy)amphetamine". J Med Chem 36 (23): 3700–3706. November 1993. doi:10.1021/jm00075a027. PMID 8246240. 
  116. ↑ 116.0 116.1 116.2 116.3 116.4 116.5 116.6 116.7 "Novel Benzofuran Derivatives Induce Monoamine Release and Substitute for the Discriminative Stimulus Effects of 3,4-Methylenedioxymethamphetamine". J Pharmacol Exp Ther 391 (1): 22–29. September 2024. doi:10.1124/jpet.123.001837. PMID 38272669. 
  117. ↑ 117.0 117.1 117.2 117.3 117.4 117.5 117.6 117.7 117.8 "Aminopropylbenzothiophenes (APBTs) are novel monoamine transporter ligands that lack stimulant effects but display psychedelic-like activity in mice". Neuropsychopharmacology 47 (4): 914–923. March 2022. doi:10.1038/s41386-021-01221-0. PMID 34750565. 
  118. ↑ 118.0 118.1 118.2 118.3 "The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue". Neuropharmacology 101: 68–75. February 2016. doi:10.1016/j.neuropharm.2015.09.004. PMID 26362361. 
  119. ↑ "Synthesis and pharmacological evaluation of ring-methylated derivatives of 3,4-(methylenedioxy)amphetamine (MDA)". J Med Chem 41 (6): 1001–1005. March 1998. doi:10.1021/jm9705925. PMID 9526575. 
  120. ↑ 120.0 120.1 120.2 120.3 "Structure-activity studies on amphetamine analogs using drug discrimination methodology". Pharmacol Biochem Behav 21 (6): 895–901. December 1984. doi:10.1016/s0091-3057(84)80071-4. PMID 6522418. 
  121. ↑ 121.0 121.1 121.2 121.3 121.4 121.5 Alberto-Silva AS, Hemmer S, Bock HA, Alves da Silva L, Scott KR, Kastner N, et al. (April 2024). "Bioisosteric analogs of MDMA with improved pharmacological profile". bioRxiv 10.1101/2024.04.08.588083.
  122. ↑ 122.0 122.1 122.2 "[Kapitel 5: Ersatz des Arylteils durch nichtaromatische Reste"] (in de). Phenethylamine: von der Struktur zur Funktion. Nachtschatten-Science. Solothurn: Nachtschatten-Verlag. 2013. pp. 289–346. ISBN 978-3-03788-700-4. OCLC 858805226. https://books.google.com/books?id=-Us1kgEACAAJ. Retrieved 29 January 2025. 
  123. ↑ 123.0 123.1 123.2 123.3 123.4 123.5 123.6 123.7 123.8 Forsyth, Andrea N (22 May 2012). Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines. https://scholarworks.uno.edu/td/1436/. Retrieved 4 November 2024. 
  124. ↑ "3,4-Methylenedioxyamphetamine (MDA) analogues exhibit differential effects on synaptosomal release of 3H-dopamine and 3H-5-hydroxytryptamine". Pharmacol Biochem Behav 38 (3): 505–512. March 1991. doi:10.1016/0091-3057(91)90005-m. PMID 1829838. 
  125. ↑ 125.0 125.1 "Behavioral and developmental effects of two 3,4-methylenedioxymethamphetamine (MDMA) derivatives". Drug Alcohol Depend 36 (3): 161–166. December 1994. doi:10.1016/0376-8716(94)90141-4. PMID 7889806. 
  126. ↑ 126.0 126.1 126.2 "[Kapitel 4: Heteroarylalkylamine"] (in de). Phenethylamine: von der Struktur zur Funktion. Nachtschatten-Science. Solothurn: Nachtschatten-Verlag. 2013. pp. 289–346. ISBN 978-3-03788-700-4. OCLC 858805226. https://books.google.com/books?id=-Us1kgEACAAJ. Retrieved 29 January 2025. 
  127. ↑ 127.0 127.1 127.2 Decker, Ann M.; Partilla, John S.; Baumann, Michael H.; Rothman, Richard B.; Blough, Bruce E. (2016). "The biogenic amine transporter activity of vinylogous amphetamine analogs". MedChemComm 7 (8): 1657–1663. doi:10.1039/C6MD00245E. ISSN 2040-2503. 
  128. ↑ 128.0 128.1 128.2 "Vinylogous phenethylamines as neurotransmitter releasers". 11 May 2017. https://patents.google.com/patent/US10899699B2/en. 
  129. ↑ 129.0 129.1 "α-PPP and its derivatives are selective partial releasers at the human norepinephrine transporter: A pharmacological characterization of interactions between pyrrolidinopropiophenones and high and low affinity monoamine transporters". Neuropharmacology 190. June 2021. doi:10.1016/j.neuropharm.2021.108570. PMID 33864800. 
  130. ↑ 130.0 130.1 "Structure-Activity Relationships of Substituted Cathinones, with Transporter Binding, Uptake, and Release". J Pharmacol Exp Ther 360 (1): 33–47. January 2017. doi:10.1124/jpet.116.236349. PMID 27799294. 
  131. ↑ 131.0 131.1 131.2 131.3 131.4 131.5 131.6 131.7 "Binding of the amphetamine-like 1-phenyl-piperazine to monoamine transporters". ACS Chem Neurosci 3 (9): 693–705. September 2012. doi:10.1021/cn300040f. PMID 23019496. 
  132. ↑ 132.0 132.1 132.2 132.3 "Novel serotonergic agents". Drug des Discov 9 (3–4): 299–312. 1993. PMID 8400010. https://bitnest.netfirms.com/external/DrugDes.Disc/9.299. 
  133. ↑ Baggott M, "2-Aminoindane compounds for mental disorders or enhancement.", WO patent 2022/032147, published 10 February 2022
  134. ↑ "A new, potent, conformationally restricted analogue of amphetamine: 2-amino-1,2-dihydronaphthalene". J Med Chem 25 (5): 535–538. May 1982. doi:10.1021/jm00347a011. PMID 6123601. 
  135. ↑ "Structural variation and (+)-amphetamine-like discriminative stimulus properties". Pharmacol Biochem Behav 38 (3): 581–586. March 1991. doi:10.1016/0091-3057(91)90017-v. PMID 2068194. 
  136. ↑ 136.0 136.1 136.2 136.3 Vekariya, Rakesh (2012). "Towards Understanding the Mechanism of Action of Abused Cathinones". VCU Theses and Dissertations. doi:10.25772/AR93-7024. 
  137. ↑ 137.00 137.01 137.02 137.03 137.04 137.05 137.06 137.07 137.08 137.09 137.10 137.11 137.12 137.13 137.14 137.15 137.16 137.17 137.18 137.19 137.20 137.21 137.22 137.23 "The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes". Psychopharmacology 236 (3): 915–924. March 2019. doi:10.1007/s00213-018-5063-9. PMID 30341459. 
  138. ↑ 138.0 138.1 & Sean Dalziel"Specialized combinations for mental disorders or mental enhancement" US patent 20240335414, published 10 October 2024
  139. ↑ 139.0 139.1 Baggott MJ, "Indolizine compounds for the treatment of mental disorders or inflammation", WO patent 2023183613A2, published 2023 September 28, assigned to Tactogen
  140. ↑ Matthew J. Baggott, "Indolizine compounds for the treatment of mental disorders or mental enhancement", WO patent 2023081306A1, published 11 May 2023, assigned to Tactogen
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  142. ↑ 142.0 142.1 142.2 "Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA)". Br J Pharmacol 154 (3): 606–622. June 2008. doi:10.1038/bjp.2008.124. PMID 18500382. 
  143. ↑ 143.0 143.1 "Effect of tuamine, heptaminol and two analogues on uptake and release of catecholamines in cultured chromaffin cells". Biochem Pharmacol 40 (4): 821–825. August 1990. doi:10.1016/0006-2952(90)90322-c. PMID 2386550. 
  144. ↑ "Methylhexaneamine causes tachycardia and pressor responses indirectly by releasing noradrenaline in the rat". Eur J Pharmacol 843: 121–125. January 2019. doi:10.1016/j.ejphar.2018.10.047. PMID 30395850. 
  145. ↑ "Octodrine: New Questions and Challenges in Sport Supplements". Brain Sci 8 (2): 34. February 2018. doi:10.3390/brainsci8020034. PMID 29461475. 
  146. ↑ 146.0 146.1 "History full circle: 'Novel' sympathomimetics in supplements". Drug Test Anal 8 (3–4): 283–286. 2016. doi:10.1002/dta.1852. PMID 27072841. 
  147. ↑ "Scientific Opinion on the Regulatory Status of 1,3-Dimethylamylamine (DMAA)". European Journal of Food Research & Review 2 (4): 93–100. 2012. http://asian.universityeprint.com/id/eprint/1287/1/Venhuis-Kaste_242012EJFRR1625.pdf. 
  148. ↑ "Structure-based discovery of prescription drugs that interact with the norepinephrine transporter, NET". Proc Natl Acad Sci U S A 108 (38): 15810–15815. September 2011. doi:10.1073/pnas.1106030108. PMID 21885739. Bibcode: 2011PNAS..10815810S. 
  149. ↑ 149.0 149.1 149.2 149.3 Partilla, John S.; Baumann, Michael H.; Decker, Ann M.; Blough, Bruce E.; Rothman, Richard B. (2016). "Interrogating the Activity of Ligands at Monoamine Transporters in Rat Brain Synaptosomes". Neurotransmitter Transporters. 118. New York, NY: Springer New York. pp. 41–52. doi:10.1007/978-1-4939-3765-3_3. ISBN 978-1-4939-3763-9. 
  150. ↑ "Development of a High-Throughput Assay for Biogenic Amine Transporter Substrates". Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc. NIDA Res Monogr. 180. 1999. pp. 1–476 (251). https://archives.nida.nih.gov/sites/default/files/180.pdf#page=260. "The major goal of this study was to establish a high-throughput assay to detect [monoamine transporter substrates (SBSTs)] for use in a project to develop new drugs with dual activity as SBSTs of DAT and SERT. METHODS. Using minor modifications of published procedures, rat brain synaptosomes were preloaded with either [3H]DA, [3H]NE or [3H]5-HT. Test drugs were added and the reaction terminated by rapid filtration over Whatman GF/B filters. Release was quantified by counting how much tritium was retained on the filters. RESULTS. Using optimized conditions known SBSTs potently decreased retained tritium in a dose-dependent manner whereas known [uptake inhibitors (UIs)] were weak or ineffective. UIs shifted SBST inhibition curves to the right, consistent with antagonist-like activity. CONCLUSION. We have developed high throughput assays which detect SBSTs for the DA, 5-HT and NE transporters." 
  151. ↑ 151.0 151.1 151.2 151.3 151.4 151.5 151.6 151.7 "Profiling CNS Stimulants with a High-Throughput Assay for Biogenic Amine Transporter Substrates". Problems of Drug Dependence 1999: Proceedings of the 61st Annual Scientific Meeting, The College on Problems of Drug Dependence, Inc. NIDA Res Monogr. 180. 1999. pp. 1–476 (252). https://archives.nida.nih.gov/sites/default/files/180.pdf#page=261. "RESULTS. Methamphetamine and amphetamine potently released NE (IC50s = 14.3 and 7.0 nM) and DA (IC50s = 40.4 nM and 24.8 nM), and were much less potent releasers of 5-HT (IC50s = 740 nM and 1765 nM). Phentermine released all three biogenic amines with an order of potency NE (IC50 = 28.8 nM)> DA (IC50 = 262 nM)> 5-HT (IC50 = 2575 nM). Aminorex released NE (IC50 = 26.4 nM), DA (IC50 = 44.8 nM) and 5-HT (IC50 = 193 nM). Chlorphentermine was a very potent 5-HT releaser (IC50 = 18.2 nM), a weaker DA releaser (IC50 = 935 nM) and inactive in the NE release assay. Chlorphentermine was a moderate potency inhibitor of [3H]NE uptake (Ki = 451 nM). Diethylpropion, which is self-administered, was a weak DA uptake inhibitor (Ki = 15 µM) and NE uptake inhibitor (Ki = 18.1 µM) and essentially inactive in the other assays. Phendimetrazine, which is self-administered, was a weak DA uptake inhibitor (IC50 = 19 µM), a weak NE uptake inhibitor (8.3 µM) and essentially inactive in the other assays." 
  152. ↑ 152.00 152.01 152.02 152.03 152.04 152.05 152.06 152.07 152.08 152.09 152.10 152.11 152.12 152.13 152.14 152.15 152.16 152.17 152.18 "Hybrid dopamine uptake blocker-serotonin releaser ligands: a new twist on transporter-focused therapeutics". ACS Med Chem Lett 5 (6): 623–627. June 2014. doi:10.1021/ml500113s. PMID 24944732. 
  153. ↑ 153.0 153.1 153.2 153.3 153.4 153.5 153.6 "DARK Classics in Chemical Neuroscience: Aminorex Analogues". ACS Chem Neurosci 9 (10): 2484–2502. October 2018. doi:10.1021/acschemneuro.8b00415. PMID 30269490. 
  154. ↑ 154.00 154.01 154.02 154.03 154.04 154.05 154.06 154.07 154.08 154.09 154.10 154.11 154.12 154.13 154.14 154.15 "Systematic Structure-Activity Studies on Selected 2-, 3-, and 4-Monosubstituted Synthetic Methcathinone Analogs as Monoamine Transporter Releasing Agents". ACS Chem Neurosci 10 (1): 740–745. January 2019. doi:10.1021/acschemneuro.8b00524. PMID 30354055. 
  155. ↑ 155.0 155.1 155.2 "Fluorinated phenmetrazine "legal highs" act as substrates for high-affinity monoamine transporters of the SLC6 family". Neuropharmacology 134 (Pt A): 149–157. May 2018. doi:10.1016/j.neuropharm.2017.10.006. PMID 28988906. 
  156. ↑ 156.0 156.1 156.2 156.3 156.4 "Synthesis, analytical characterization, and monoamine transporter activity of the new psychoactive substance 4-methylphenmetrazine (4-MPM), with differentiation from its ortho- and meta- positional isomers". Drug Test Anal 10 (9): 1404–1416. September 2018. doi:10.1002/dta.2396. PMID 29673128. 
  157. ↑ 157.00 157.01 157.02 157.03 157.04 157.05 157.06 157.07 157.08 157.09 "Phenylmorpholines and analogues thereof". 20 May 2011. https://patents.google.com/patent/WO2011146850A1/en. 
  158. ↑ 158.0 158.1 158.2 158.3 "Pharmacological examination of trifluoromethyl ring-substituted methcathinone analogs". Eur J Pharmacol 699 (1–3): 180–187. January 2013. doi:10.1016/j.ejphar.2012.11.008. PMID 23178523. 
  159. ↑ 159.0 159.1 159.2 Cozzi, Nicholas V.; Daley, Paul F.; Evans, Darin L.; Partilla, John S.; Rothman, Richard B.; Ruoho, Arnold E.; Baumann, Michael H. (2011). "Trifluoromethyl ring-substituted methcathinone analogs: activity at monoamine uptake transporters". The FASEB Journal 25 (S1). doi:10.1096/fasebj.25.1_supplement.1083.1. ISSN 0892-6638. 
  160. ↑ 160.0 160.1 160.2 160.3 160.4 160.5 "Behavioral and neurochemical pharmacology of six psychoactive substituted phenethylamines: mouse locomotion, rat drug discrimination and in vitro receptor and transporter binding and function". Psychopharmacology (Berl) 231 (5): 875–888. March 2014. doi:10.1007/s00213-013-3303-6. PMID 24142203. 
  161. ↑ 161.00 161.01 161.02 161.03 161.04 161.05 161.06 161.07 161.08 161.09 161.10 Shalabi AR (14 December 2017). Structure-Activity Relationship Studies of Bupropion and Related 3-Substituted Methcathinone Analogues at Monoamine Transporters. VCU Scholars Compass (Thesis). doi:10.25772/M4E1-3549. Retrieved 24 November 2024.
  162. ↑ 162.0 162.1 "Norfenfluramine to treat dravet syndrome". 9 March 2023. https://patents.google.com/patent/US20230076320A1/en. 
  163. ↑ 163.0 163.1 163.2 163.3 "Deconstructed Analogues of Bupropion Reveal Structural Requirements for Transporter Inhibition versus Substrate-Induced Neurotransmitter Release". ACS Chem Neurosci 8 (6): 1397–1403. June 2017. doi:10.1021/acschemneuro.7b00055. PMID 28220701. 
  164. ↑ "Bupropion and bupropion analogs as treatments for CNS disorders". Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Adv Pharmacol. 69. 2014. pp. 177–216. doi:10.1016/B978-0-12-420118-7.00005-6. ISBN 978-0-12-420118-7. 
  165. ↑ 165.0 165.1 Namjoshi, Ojas A.; Decker, Ann M.; Landavazo, Antonio; Partilla, John S.; Baumann, Michael H.; Rothman, Richard B.; Blough, Bruce E. (2015). "Chemical modifications to alter monoamine releasing activity of phenmetrazine analogs as potential treatments of stimulant addiction". Drug and Alcohol Dependence 146: e48. doi:10.1016/j.drugalcdep.2014.09.502. 
  166. ↑ "Effects of methcathinone and 3-Cl-methcathinone (PAL-434) in cocaine discrimination or self-administration in rhesus monkeys". Int J Neuropsychopharmacol 16 (9): 1985–1998. October 2013. doi:10.1017/S146114571300059X. PMID 23768644. 
  167. ↑ 167.0 167.1 167.2 167.3 "Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs". The Journal of Pharmacology and Experimental Therapeutics 313 (2): 848–854. May 2005. doi:10.1124/jpet.104.080101. PMID 15677348. 
  168. ↑ "Selective suppression of cocaine- versus food-maintained responding by monoamine releasers in rhesus monkeys: benzylpiperazine, (+)phenmetrazine, and 4-benzylpiperidine". J Pharmacol Exp Ther 329 (1): 272–281. April 2009. doi:10.1124/jpet.108.143701. PMID 19151247. 
  169. ↑ 169.0 169.1 169.2 169.3 169.4 "Neuropharmacology of Synthetic Cathinones". New Psychoactive Substances. Handbook of Experimental Pharmacology. 252. 2018. 113–142. doi:10.1007/164_2018_178. ISBN 978-3-030-10560-0. 
  170. ↑ 170.00 170.01 170.02 170.03 170.04 170.05 170.06 170.07 170.08 170.09 Sakloth F (11 December 2015). Psychoactive synthetic cathinones (or 'bath salts'): Investigation of mechanisms of action. VCU Scholars Compass (Thesis). doi:10.25772/AY8R-PW77. Retrieved 24 November 2024.
  171. ↑ 171.0 171.1 171.2 171.3 171.4 171.5 "Quantitative structure-activity relationship analysis of the pharmacology of para-substituted methcathinone analogues". Br J Pharmacol 172 (10): 2433–2444. May 2015. doi:10.1111/bph.13030. PMID 25438806. 
  172. ↑ 172.00 172.01 172.02 172.03 172.04 172.05 172.06 172.07 172.08 172.09 172.10 "Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones". Neuropharmacology 245. March 2024. doi:10.1016/j.neuropharm.2023.109827. PMID 38154512. 
  173. ↑ 173.0 173.1 173.2 173.3 Nicole, Lauren (2022). "In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones". https://www.proquest.com/openview/a207e98868b4a9c5ac9296fb24abbcd8/. "FIGURE 2-6: Release: Effects of the specified test drug on monoamine release by DAT (red circles), NET (blue squares), and SERT (black traingles) in rat brain tissue. [...] EC50 values determined for the drug indicated within the panel. [...]" 
  174. ↑ 174.0 174.1 174.2 "Characterization of a novel and potentially lethal designer drug (±)-cis-para-methyl-4-methylaminorex (4,4'-DMAR, or 'Serotoni')". Drug Testing and Analysis 6 (7–8): 684–695. 2014. doi:10.1002/dta.1668. PMID 24841869. 
  175. ↑ 175.0 175.1 175.2 175.3 175.4 "N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability". Neuropsychopharmacology 42 (10): 1950–1961. September 2017. doi:10.1038/npp.2017.98. PMID 28530234. 
  176. ↑ "p-methylthioamphetamine is a potent new non-neurotoxic serotonin-releasing agent". Eur J Pharmacol 229 (1): 31–38. December 1992. doi:10.1016/0014-2999(92)90282-9. PMID 1473561. 
  177. ↑ "4-Methylthioamphetamine increases dopamine in the rat striatum and has rewarding effects in vivo". Basic Clin Pharmacol Toxicol 111 (6): 371–379. December 2012. doi:10.1111/j.1742-7843.2012.00926.x. PMID 22788961. 
  178. ↑ 178.0 178.1 178.2 "Monoamine transporter and receptor interaction profiles of a new series of designer cathinones". Neuropharmacology 79: 152–160. April 2014. doi:10.1016/j.neuropharm.2013.11.008. PMID 24275046. 
  179. ↑ 179.0 179.1 179.2 "The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The "Phenylalkylaminome" with a Focus on Selected Drugs of Abuse". J Med Chem 60 (7): 2605–2628. April 2017. doi:10.1021/acs.jmedchem.7b00085. PMID 28244748. "Table 5. Action of MDMA, MDA, and PMMA as Releasing Agents at the Serotonin (SERT), Dopamine (DAT), and Norepinephrine (NET) Transporters18,59,60 [...] a Data, although from different publications, were obtained from the same laboratory.". 
  180. ↑ 180.0 180.1 180.2 180.3 "Synthesis, characterization, and monoamine transporter activity of the new psychoactive substance 3',4'-methylenedioxy-4-methylaminorex (MDMAR)". Drug Testing and Analysis 7 (7): 555–564. July 2015. doi:10.1002/dta.1732. PMID 25331619. 
  181. ↑ 181.0 181.1 181.2 181.3 181.4 181.5 "A "Furious" Effort to Develop Novel 3,4-Methylenedioxymethamphetamine-Like Therapeutics". J Pharmacol Exp Ther 391 (1): 18–21. September 2024. doi:10.1124/jpet.124.002183. PMID 39293859. 
  182. ↑ 182.0 182.1 182.2 "Advantageous benzofuran compositions for mental disorders or enhancement". 8 December 2022. https://patents.google.com/patent/US11767305B2/. 
  183. ↑ 183.0 183.1 "Investigation of the Optical Isomers of Methcathinone, and Two Achiral Analogs, at Monoamine Transporters and in Intracranial Self-Stimulation Studies in Rats". ACS Chem Neurosci 11 (12): 1762–1769. June 2020. doi:10.1021/acschemneuro.9b00617. PMID 32356961. 
  184. ↑ 184.0 184.1 Nguyen, Vy (2019). "Analyzing Interactions Between Methcathinone Analogs and the Human Monoamine Transporters". VCU Theses and Dissertations. doi:10.25772/T1DW-MG60. 
  185. ↑ 185.0 185.1 185.2 185.3 Davies RA (10 July 2019). Structure-Activity Relationship Studies of Synthetic Cathinones and Related Agents. VCU Scholars Compass (Thesis). doi:10.25772/TZSA-0396. Retrieved 24 November 2024.
  186. ↑ "The Biogenic Amine Transporter Properties of Selected Shulgin Tryptamines (Abstract 50)". 69th CPDD Annual Scientific Meeting. Quebec City, Quebec, Canada: College on Problems of Drug Dependence. June 2007. https://scholar.google.com/scholar?cluster=15000993145639559294. 
  187. ↑ 187.0 187.1 187.2 187.3 Yadav BJ (16 July 2019). Understanding Structure–Activity Relationship of Synthetic Cathinones (Bath Salts) Utilizing Methylphenidate. VCU Scholars Compass (Thesis). doi:10.25772/MJQW-8C64. Retrieved 24 November 2024.
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  189. ↑ 189.0 189.1 189.2 189.3 189.4 "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology 38 (4): 552–562. March 2013. doi:10.1038/npp.2012.204. PMID 23072836. 
  190. ↑ 190.00 190.01 190.02 190.03 190.04 190.05 190.06 190.07 190.08 190.09 Cite error: Invalid <ref> tag; no text was provided for refs named GlennonDukat2017
  191. ↑ Liu, Yi (28 March 2018). Structural Determinants for Inhibitor Recognition by the Dopamine Transporter. https://dsc.duq.edu/etd/829/. Retrieved 11 December 2024. "The most commonly studied DAT substrates are amphetamines, including amphetamine and methamphetamine (Fig. 9). S-(+)-amphetamine releases dopamine with an EC50 of 8.7 nM; the R-(−)-amphetamine is 3-fold weaker, at 27.7 nM (EC50) (Blough, Page et al. 2005). Although weaker, a similar trend is seen for the optical isomers of methamphetamine. S-(+)-methamphetamine releases dopamine with an EC50 of 24.5 nM, while the R-(−)-methamphetamine is 16-fold less active at 416 nM (EC50) (Blough, Page et al. 2005). [...] Blough, B. E., K. M. Page, et al. (2005). "Struture-activity relationship studies of DAT, SERT, and NET releasers." New Perspectives on Neurotransmitter Transporter Pharmacology.". 
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  193. ↑ 193.0 193.1 "N-substituted piperazines abused by humans mimic the molecular mechanism of 3,4-methylenedioxymethamphetamine (MDMA, or 'Ecstasy')". Neuropsychopharmacology 30 (3): 550–560. March 2005. doi:10.1038/sj.npp.1300585. PMID 15496938. 
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  197. ↑ 197.0 197.1 "The synthetic cathinones, butylone and pentylone, are stimulants that act as dopamine transporter blockers but 5-HT transporter substrates". Psychopharmacology (Berl) 236 (3): 953–962. March 2019. doi:10.1007/s00213-018-5075-5. PMID 30345459. 
  198. ↑ "Substituted methcathinones differ in transporter and receptor interactions". Biochem Pharmacol 85 (12): 1803–1815. June 2013. doi:10.1016/j.bcp.2013.04.004. PMID 23583454. 
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  200. ↑ 200.0 200.1 200.2 200.3 200.4 200.5 200.6 200.7 200.8 "In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates". The Journal of Pharmacology and Experimental Therapeutics 307 (1): 138–145. October 2003. doi:10.1124/jpet.103.053975. PMID 12954796. 
  201. ↑ 201.0 201.1 201.2 "Amphetamine-like Neurochemical and Cardiovascular Effects of α-Ethylphenethylamine Analogs Found in Dietary Supplements". J Pharmacol Exp Ther 376 (1): 118–126. January 2021. doi:10.1124/jpet.120.000129. PMID 33082158. 
  202. ↑ 202.0 202.1 202.2 202.3 "Eutylone and Its Structural Isomers Interact with Monoamine Transporters and Induce Locomotor Stimulation". ACS Chem Neurosci 12 (7): 1170–1177. April 2021. doi:10.1021/acschemneuro.0c00797. PMID 33689284. 
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  204. ↑ 204.0 204.1 "Analytical quantification, intoxication case series, and pharmacological mechanism of action for N-ethylnorpentylone (N-ethylpentylone or ephylone)". Drug Test Anal 11 (3): 461–471. March 2019. doi:10.1002/dta.2502. PMID 30207090. 
  205. ↑ 205.0 205.1 205.2 205.3 205.4 205.5 205.6 "(+)-Fenfluramine and its major metabolite, (+)-norfenfluramine, are potent substrates for norepinephrine transporters". The Journal of Pharmacology and Experimental Therapeutics 305 (3): 1191–1199. June 2003. doi:10.1124/jpet.103.049684. PMID 12649307. 
  206. ↑ 206.0 206.1 206.2 206.3 206.4 206.5 206.6 206.7 "3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro". Molecular Pharmacology 63 (6): 1223–1229. June 2003. doi:10.1124/mol.63.6.1223. PMID 12761331. 
  207. ↑ 207.0 207.1 Eisenberg R, ed (June 2006). "Interaction of MDMA and its Metabolites at Monoamine Transporters in Rat Brain (Abstract 60)". 68th Annual Scientific Meeting of The College on Problems of Drug Dependence, June 17–22, 2006, Fairmont Scottsdale Princess, Scottsdale, Arizona. p. 15. https://cpdd.org/wp-content/uploads/2015/04/2006abstractbook.pdf#page=16. "As expected, MDMA was a potent substrate at SERT (90±7 nM) and DAT (249±19 nM). HHMA was a potent DAT substrate (130±6 nM) but weaker at SERT (1729 ±134). HMMA displayed weak activity at both SERT (607±50 nM) and DAT (3652±252 nM)." 
  208. ↑ 208.0 208.1 208.2 208.3 "Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats". Neuropsychopharmacology 42 (3): 649–660. February 2017. doi:10.1038/npp.2016.213. PMID 27658484. 
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  212. ↑ 212.0 212.1 212.2 212.3 "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology 37 (5): 1192–1203. April 2012. doi:10.1038/npp.2011.304. PMID 22169943. 
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  219. ↑ "Development of a rationally designed, low abuse potential, biogenic amine releaser that suppresses cocaine self-administration". The Journal of Pharmacology and Experimental Therapeutics 313 (3): 1361–1369. June 2005. doi:10.1124/jpet.104.082503. PMID 15761112. 
  220. ↑ "Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters". Br J Pharmacol 173 (17): 2657–2668. September 2016. doi:10.1111/bph.13547. PMID 27391165. 
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  222. ↑ 222.0 222.1 "Drug Discrimination and Mechanisms of Drug Action". Drug Discrimination. Wiley. 5 August 2011. pp. 183–216. doi:10.1002/9781118023150.ch6. ISBN 978-0-470-43352-2. "PMMA is a 5-HT releasing agent. S(+)PMMA is a potent releaser of 5-HT (EC50 = 41 nM) and NE (EC50 = 147 nM) with reduced activity as a releaser of DA (EC50 = 1,000 nM); the R(−)isomer of PMMA is a releaser of 5-HT (EC50 = 134 nM) with reduced potency for release of NE (EC50 = 1,600 nM) and DA (EC50 > 14,000 nM) (R.B. Rothman, unpublished data)." 
  223. ↑ 223.0 223.1 223.2 223.3 223.4 223.5 223.6 223.7 "Interaction of the anorectic medication, phendimetrazine, and its metabolites with monoamine transporters in rat brain". European Journal of Pharmacology 447 (1): 51–57. June 2002. doi:10.1016/s0014-2999(02)01830-7. PMID 12106802. 
  224. ↑ "Appetite suppressants as agonist substitution therapies for stimulant dependence". Ann N Y Acad Sci 965 (1): 109–126. June 2002. doi:10.1111/j.1749-6632.2002.tb04155.x. PMID 12105089. Bibcode: 2002NYASA.965..109R. 
  225. ↑ "Effects of N-Alkyl-4-Methylamphetamine Optical Isomers on Plasma Membrane Monoamine Transporters and Abuse-Related Behavior". ACS Chem Neurosci 9 (7): 1829–1839. July 2018. doi:10.1021/acschemneuro.8b00138. PMID 29697951. 
  226. ↑ "Serotonin transporters, serotonin release, and the mechanism of fenfluramine neurotoxicity". Ann N Y Acad Sci 914 (1): 172–186. September 2000. doi:10.1111/j.1749-6632.2000.tb05194.x. PMID 11085319. Bibcode: 2000NYASA.914..172B. 
  227. ↑ "Neurochemical and Cardiovascular Effects of 4-Chloro Ring-Substituted Synthetic Cathinones in Rats". J Pharmacol Exp Ther 385 (3): 162–170. June 2023. doi:10.1124/jpet.122.001478. PMID 36669877. 



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