Chemistry:Monoamine releasing agent

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Short description: Class of compounds
Amphetamine, the prototypical monoamine releasing agent, which acts on norepinephrine and dopamine.

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.

Types of MRAs

MRAS can be classified by the monoamines they mainly release, although these drugs lie on a spectrum.

Mechanism of action

MRAs cause the release of monoamine neurotransmitters by various complex mechanism of actions. They may enter the presynaptic neuron primarily via plasma membrane transporters, such as the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT). Some, such as exogenous phenethylamine, amphetamine, and methamphetamine, can also diffuse directly across the cell membrane to varying degrees. Once inside the presynaptic neuron, they may inhibit the reuptake of monoamine neurotransmitters through vesicular monoamine transporter 2 (VMAT2) and release the neurotransmitters stores of synaptic vesicles into the cytoplasm by inducing reverse transport at VMAT2. MRAs can also bind to the intracellular receptor TAAR1 as agonists, which triggers a phosphorylation cascade via protein kinases that results in the phosphorylation of monoamine transporters located at the plasma membrane (i.e., the dopamine transporter, norepinephrine transporter, and serotonin transporter); upon phosphorylation, these transporters transport monoamines in reverse (i.e., they move monoamines from the neuronal cytoplasm into the synaptic cleft).[1] The combined effects of MRAs at VMAT2 and TAAR1 result in the release of neurotransmitters out of synaptic vesicles and the cell cytoplasm into the synaptic cleft where they bind to their associated presynaptic autoreceptors and postsynaptic receptors. Certain MRAs interact with other presynaptic intracellular receptors which promote monoamine neurotransmission as well (e.g., methamphetamine is also an agonist at σ1 receptor).

Effects

Monoamine releasing agents can have a wide variety of effects depending upon their selectivity for monoamines. Selective serotonin releasing agents such as fenfluramine and related compounds are described as dysphoric and lethargic in lower doses, and in higher doses some hallucinogenic effects have been reported.[2][3] Less selective serotonergic agents that stimulate an efflux in dopamine, such as MDMA are described as more pleasant, increasing energy, sociability and elevating mood.[4] Dopamine releasing agents, usually selective for both norepinephrine and dopamine have psychostimulant effect, causing an increase in energy, and elevated mood.[5] Other variables can significantly affect the subjective effects, such as infusion rate(increasing positive effects of cocaine), and expectancy.[6] Selectively noradrenergic drugs are minimally psychoactive, but as demonstrated by ephedrine may be distinguished from placebo, and trends towards liking.[7] They may also be ergogenic,[8] in contrast to reboxetine which is solely a reuptake inhibitor.[9][10]

Selectivity

MRAs act to varying extents on serotonin, norepinephrine, and dopamine. Some induce the release of all three neurotransmitters to a similar degree, like MDMA, while others are more selective. As examples, amphetamine and methamphetamine are NDRAs but only very weak releasers of serotonin (~60- and 30-fold less than dopamine, respectively) and MBDB is a fairly balanced SNRA but a weak releaser of dopamine (~6- and 10-fold lower for dopamine than norepinephrine or serotonin, respectively). Even more selective include agents like fenfluramine, a selective SRA, and ephedrine, a selective NRA. The differences in selectivity of these agents 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 via the TAAR1 and VMAT2 proteins.

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.[11] Several selective SDRAs are known however, though these compounds also act as non-selective serotonin receptor agonists.[12]

Activity profiles

Activity profiles of MRAs (EC50, nM)[13][14]
Compound 5-HT NE DA Type Class Ref
2C-E >100000 >100000 >100000 IA Phenethylamine [15]
2C-I >100000 >100000 >100000 IA Phenethylamine [15]
3-Chloromethcathinone ND ND 46.8 ND Cathinone [16]
3-Fluoroamphetamine 1937 16.1 24.2 NDRA Amphetamine [17]
3-Methylamphetamine 218 18.3 33.3 NDRA Amphetamine [17]
4-Fluoroamphetamine 730–939 28.0–37 51.5–200 NDRA Amphetamine [17][15]
cis-4-Methylaminorex 53.2 4.8 1.7 NDRA Aminorex [18]
4-Methylamphetamine 53.4 22.2 44.1 SNDRA Amphetamine [17]
4-Methylphenethylamine ND ND 271 ND Phenethylamine [16]
4-Methylthiomethamphetamine 21 ND ND ND Amphetamine [19]
4,4'-Dimethylaminorex ND ND ND SNDRA Aminorex ND
  cis-4,4'-Dimethylaminorex 17.7–18.5 11.8–26.9 8.6–10.9 SNDRA Aminorex [18][20]
  trans-4,4'-Dimethylaminorex 59.9 31.6 24.4 SNDRA Aminorex [20]
5-(2-Aminopropyl)indole 28–104.8 13.3–79 12.9–173 SNDRA Amphetamine [12][21]
  (R)-5-(2-Aminopropyl)indole 177 81 1062 SNRA Amphetamine [12]
  (S)-5-(2-Aminopropyl)indole ND ND ND SNDRA Amphetamine ND
5-Chloro-αMT 16 3434 54 SDRA Tryptamine [12]
5-Fluoro-αMT 19 126 32 SNDRA Tryptamine [12]
5-MeO-αMT 460 8900 1500 SNDRA Tryptamine [15]
5-MeO-DMT >100000 >100000 >100000 IA Tryptamine [15]
6-(2-Aminopropyl)indole 19.9 25.6 164.0 SNDRA Amphetamine [21]
Adderall ND ND ND NDRA Amphetamine ND
α-Methyltryptamine 68 79 180 SNDRA Tryptamine [15]
Amfepramone (diethylpropion) >10000 >10000 >10000 PD Cathinone [22]
Aminorex 193–414 15.1–26.4 9.1–49.4 SNDRA Aminorex [23][18]
Amphetamine ND ND ND NDRA Amphetamine ND
  D-Amphetamine 698–1765 6.6–7.2 5.8–24.8 NDRA Amphetamine [23][24]
  L-Amphetamine ND ND ND NRA Amphetamine ND
β-Ketophenethylamine ND ND 208 ND Phenethylamine [16]
BDB 180 540 2,300 NDRA Amphetamine [15]
Benzylpiperazine ≥6050 62–68 175–600 NDRA Arylpiperazine [15][25][14]
Butylamphetamine ND ND IA ND Amphetamine [16]
Cathinone ND ND ND NDRA Cathinone ND
  D-Cathinone ND ND ND NRA Cathinone ND
  L-Cathinone 2366 12.4 18.5 NDRA Cathinone [26]
Chlorphentermine 30.9 >10000 2650 SRA Amphetamine [23]
DMPP 26 56 1207 SNRA Arylpiperazine [19]
Dopamine >10000 66.2 86.9 NDRA Phenethylamine [23]
DPT >100000 >100000 >100000 IA Tryptamine [15]
Ephedrine ND ND ND NDRA Cathinol ND
  D-Ephedrine >10000 43.1–72.4 236–1350 NDRA Cathinol [23]
  L-Ephedrine >10000 218 2104 NRA Cathinol [23][26]
Epinephrine ND ND ND NDRA Phenethylamine ND
Ethcathinone 2118 99.3 >1000 NRA Cathinone [22]
Ethylamphetamine ND ND 296 ND Amphetamine [16]
Fenfluramine 79.3–108 739 >10000 SRA Amphetamine [23][27][28]
  D-Fenfluramine 51.7 302 >10000 SNRA Amphetamine [23][27]
  L-Fenfluramine 147 >10000 >10000 SRA Amphetamine [27][29]
MBDB 540 3300 >100,000 SNRA Amphetamine [15]
mCPP 28–38.1 ≥1400 63000 SRA Arylpiperazine [15][29][30]
MDA 160 108 190 SNDRA Amphetamine [28]
  (R)-MDA 310 290 900 SNDRA Amphetamine [28]
  (S)-MDA 100 50 98 SNDRA Amphetamine [28]
MDEA 47 2608 622 SNDRA Amphetamine [19]
  (R)-MDEA 52 651 507 SNDRA Amphetamine [19]
  (S)-MDEA 465 RI RI SRA Amphetamine [19]
MDMA 49.6–72 54.1–110 51.2–278 SNDRA Amphetamine [23][31][21][28]
  (''R'')-MDMA 340 560 3700 SNDRA Amphetamine [28]
  (''S'')-MDMA 74 136 142 SNDRA Amphetamine [28]
MDMAR ND ND ND SNDRA Aminorex ND
  cis-MDMAR 43.9 14.8 10.2 SNDRA Aminorex [20]
  trans-MDMAR 73.4 38.9 36.2 SNDRA Aminorex [20]
Mephedrone 118.3–122 58–62.7 49.1–51 SNDRA Cathinone [31][24]
Methamnetamine 13 34 10 SNDRA Amphetamine [19]
Methamphetamine ND ND ND NDRA Amphetamine ND
  D-Methamphetamine 736–1291.7 12.3–13.8 8.5–24.5 NDRA Amphetamine [23][31]
  L-Methamphetamine 4640 28.5 416 NRA Amphetamine [23]
Methcathinone ND ND ND NDRA Cathinone ND
  D-Methcathinone ND ND ND NRA Cathinone ND
  L-Methcathinone 1772 13.1 14.8 NDRA Cathinone [26]
Methylone 234–242.1 140–152.3 117–133.0 SNDRA Cathinone [31][24]
Naphthylisopropylamine 3.4 11.1 12.6 SNDRA Amphetamine [32]
Norephedrine ND ND ND NDRA Cathinol ND
  D-Norephedrine >10000 42.1 302 NDRA Cathinol [26]
  L-Norephedrine (phenylpropanolamine) >10000 137 1371 NRA Cathinol [26]
Norepinephrine >10000 164 869 NDRA Phenethylamine [23]
Norfenfluramine 104 168–170 1900–1925 SNRA Amphetamine [27][28]
Norpropylhexedrine ND ND ND NDRA Cyclohexethylamine ND
  D-Norpropylhexedrine ND ND ND NRA Cyclohexethylamine ND
  L-Norpropylhexedrine ND ND ND NDRA Cyclohexethylamine ND
Norpseudoephedrine ND ND ND NDRA Cathinol ND
  D-Norpseudoephedrine (cathine) >10000 15.0 68.3 NDRA Cathinol [26]
  L-Norpseudoephedrine >10000 30.1 294 NDRA Cathinol [26]
oMPP 175 39.1 296–542 SNDRA Arylpiperazine [33][16]
PAL-738 23 65 58 SNDRA Phenylmorpholine [19]
Phenethylamine ND ND 39.5 NDRA Phenethylamine [16]
Phendimetrazine >100000 >10000 >10000 PD Phenylmorpholine [34]
Phenmetrazine 7765 50.4 131 NDRA Phenylmorpholine [34]
Phentermine 3511 39.4 262 NDRA Amphetamine [23]
Phenylalaninol ND ND ND ND Amphetamine ND
  D-Phenylalaninol >10000 106 1355 NRA Amphetamine [33]
  L-Phenylalaninol ND ND ND ND Amphetamine ND
Phenylisobutylamine ND ND 225 ND Amphetamine [16]
pMPP 3200 1500 11000 SNRA Arylpiperazine [15]
pNPP 43 >10000 >10000 SRA Arylpiperazine [19]
Propylamphetamine ND ND RI (1013) ND Amphetamine [16]
Propylhexedrine ND ND ND NDRA Cyclohexethylamine ND
  D-Propylhexedrine ND ND ND NRA Cyclohexethylamine ND
  L-Propylhexedrine ND ND ND NDRA Cyclohexethylamine ND
Pseudoephedrine ND ND ND NDRA Cathinol ND
  D-Pseudoephedrine >10000 4092 9125 NDRA Cathinol [26]
  L-Pseudoephedrine >10000 224 1988 NRA Cathinol [26]
Pseudophenmetrazine >10000 514 RI NRA Phenylmorpholine [34]
Psilocin 561 >10000 >10000 SRA Tryptamine [19]
Serotonin 44.4 >10000 >10000 SRA Tryptamine [23]
TFMPP 121 ND >10000 SRA Arylpiperazine [25]
TFMCPP 33 >10000 >10000 SRA Arylpiperazine [19]
Trimethoxyamphetamine 16000 >100000 >100000 IA Amphetamine [15]
Tyramine 2775 40.6 119 NDRA Phenethylamine [23]
The smaller the value, the more strongly the substance activates or releases the neurotransmitter.

See also

  • Monoamine reuptake inhibitor
  • Release modulator

References

  1. ↑ "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". Journal of Neurochemistry 116 (2): 164–76. January 2011. doi:10.1111/j.1471-4159.2010.07109.x. PMID 21073468. 
  2. ↑ Brust, John Calvin M. (2004). Neurological Aspects of Substance Abuse. Butterworth-Heinemann. pp. 117–. ISBN 978-0-7506-7313-6. https://books.google.com/books?id=fOfxoQm_a7MC&pg=PA117. 
  3. ↑ United States. Congress. Senate. Select Committee on Small Business. Subcommittee on Monopoly and Anticompetitive Activities (1976). 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. pp. 2–. https://books.google.com/books?id=Rs1GAQAAMAAJ&pg=RA2-PA56. 
  4. ↑ Parrott, A. C.; Stuart, M. (1 September 1997). "Ecstasy (MDMA), amphetamine, and LSD: comparative mood profiles in recreational polydrug users" (in en). Human Psychopharmacology: Clinical and Experimental 12 (5): 501–504. doi:10.1002/(sici)1099-1077(199709/10)12:5<501::aid-hup913>3.3.co;2-m. ISSN 1099-1077. 
  5. ↑ "The drug effects questionnaire: psychometric support across three drug types". Psychopharmacology 227 (1): 177–92. May 2013. doi:10.1007/s00213-012-2954-z. PMID 23271193. 
  6. ↑ "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. 
  7. ↑ "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): 447–55. September 2001. doi:10.1007/s002280100317. PMID 11699608. 
  8. ↑ "Ephedra and its application to sport performance: another concern for the athletic trainer?". Journal of Athletic Training 36 (4): 420–4. October 2001. PMID 16558668. 
  9. ↑ "Central fatigue: the serotonin hypothesis and beyond". Sports Medicine 36 (10): 881–909. 1 January 2006. doi:10.2165/00007256-200636100-00006. PMID 17004850. 
  10. ↑ "Alterations in central fatigue by pharmacological manipulations of neurotransmitters in normal and high ambient temperature". Sports Medicine 40 (3): 229–46. March 2010. doi:10.2165/11533670-000000000-00000. PMID 20199121. https://www.researchgate.net/publication/41720970. 
  11. ↑ "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. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 "Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys". Exp Clin Psychopharmacol 22 (3): 274–284. 2014. doi:10.1037/a0036595. PMID 24796848. 
  13. ↑ "Monoamine transporters and psychostimulant drugs". Eur. J. Pharmacol. 479 (1–3): 23–40. 2003. doi:10.1016/j.ejphar.2003.08.054. PMID 14612135. 
  14. ↑ 14.0 14.1 "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry 6 (17): 1845–59. 2006. doi:10.2174/156802606778249766. PMID 17017961. https://zenodo.org/record/1235860. 
  15. ↑ 15.00 15.01 15.02 15.03 15.04 15.05 15.06 15.07 15.08 15.09 15.10 15.11 15.12 "The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain". Eur. J. Pharmacol. 559 (2–3): 132–7. 2007. doi:10.1016/j.ejphar.2006.11.075. PMID 17223101. 
  16. ↑ 16.0 16.1 16.2 16.3 16.4 16.5 16.6 16.7 16.8 "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug Alcohol Depend 147: 1–19. 2015. doi:10.1016/j.drugalcdep.2014.12.005. PMID 25548026. 
  17. ↑ 17.0 17.1 17.2 17.3 "Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs". The Journal of Pharmacology and Experimental Therapeutics 313 (2): 848–54. May 2005. doi:10.1124/jpet.104.080101. PMID 15677348. 
  18. ↑ 18.0 18.1 18.2 "Characterization of a novel and potentially lethal designer drug (±)-cis-para-methyl-4-methylaminorex (4,4'-DMAR, or 'Serotoni')". Drug Test Anal 6 (7–8): 684–95. 2014. doi:10.1002/dta.1668. PMID 24841869. 
  19. ↑ 19.0 19.1 19.2 19.3 19.4 19.5 19.6 19.7 19.8 19.9 "Studies of the biogenic amine transporters. 14. Identification of low-efficacy "partial" substrates for the biogenic amine transporters". J. Pharmacol. Exp. Ther. 341 (1): 251–62. 2012. doi:10.1124/jpet.111.188946. PMID 22271821. 
  20. ↑ 20.0 20.1 20.2 20.3 "Synthesis, characterization, and monoamine transporter activity of the new psychoactive substance 3',4'-methylenedioxy-4-methylaminorex (MDMAR)". Drug Test Anal 7 (7): 555–64. 2015. doi:10.1002/dta.1732. PMID 25331619. 
  21. ↑ 21.0 21.1 21.2 "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. 2016. doi:10.1016/j.neuropharm.2015.09.004. PMID 26362361. 
  22. ↑ 22.0 22.1 "Uptake and release effects of diethylpropion and its metabolites with biogenic amine transporters". Bioorg. Med. Chem. 8 (12): 2689–92. 2000. doi:10.1016/s0968-0896(00)00210-8. PMID 11131159. 
  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 "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. 
  24. ↑ 24.0 24.1 24.2 "Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products". Neuropsychopharmacology 38 (4): 552–62. 2013. doi:10.1038/npp.2012.204. PMID 23072836. 
  25. ↑ 25.0 25.1 "N-substituted piperazines abused by humans mimic the molecular mechanism of 3,4-methylenedioxymethamphetamine (MDMA, or 'Ecstasy')". Neuropsychopharmacology 30 (3): 550–60. 2005. doi:10.1038/sj.npp.1300585. PMID 15496938. 
  26. ↑ 26.0 26.1 26.2 26.3 26.4 26.5 26.6 26.7 26.8 "In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates". J. Pharmacol. Exp. Ther. 307 (1): 138–45. 2003. doi:10.1124/jpet.103.053975. PMID 12954796. 
  27. ↑ 27.0 27.1 27.2 27.3 "(+)-Fenfluramine and its major metabolite, (+)-norfenfluramine, are potent substrates for norepinephrine transporters". J. Pharmacol. Exp. Ther. 305 (3): 1191–9. 2003. doi:10.1124/jpet.103.049684. PMID 12649307. 
  28. ↑ 28.0 28.1 28.2 28.3 28.4 28.5 28.6 28.7 "3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro". Mol. Pharmacol. 63 (6): 1223–9. 2003. doi:10.1124/mol.63.6.1223. PMID 12761331. 
  29. ↑ 29.0 29.1 "Therapeutic and adverse actions of serotonin transporter substrates". Pharmacol. Ther. 95 (1): 73–88. 2002. doi:10.1016/s0163-7258(02)00234-6. PMID 12163129. 
  30. ↑ "Serotonin releasing agents. Neurochemical, therapeutic and adverse effects". Pharmacol. Biochem. Behav. 71 (4): 825–36. 2002. doi:10.1016/s0091-3057(01)00669-4. PMID 11888573. https://zenodo.org/record/1259765. 
  31. ↑ 31.0 31.1 31.2 31.3 "The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue". Neuropsychopharmacology 37 (5): 1192–203. 2012. doi:10.1038/npp.2011.304. PMID 22169943. 
  32. ↑ "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): 1361–9. June 2005. doi:10.1124/jpet.104.082503. PMID 15761112. 
  33. ↑ 33.0 33.1 "Cocaine-like discriminative stimulus effects of "norepinephrine-preferring" monoamine releasers: time course and interaction studies in rhesus monkeys". Psychopharmacology 234 (23–24): 3455–3465. 2017. doi:10.1007/s00213-017-4731-5. PMID 28889212. 
  34. ↑ 34.0 34.1 34.2 "Interaction of the anorectic medication, phendimetrazine, and its metabolites with monoamine transporters in rat brain". Eur. J. Pharmacol. 447 (1): 51–7. 2002. doi:10.1016/s0014-2999(02)01830-7. PMID 12106802. https://zenodo.org/record/1259577. 

External links



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