Chemistry:Para-Chloroamphetamine

From HandWiki
Short description: Chemical compound

Not to be confused with para-Chloromethamphetamine.
para-Chloroamphetamine
Clinical data
Other namesPCA; pCA; p-Chloroamphetamine; 4-Chloroamphetamine; 4-CA; Ro 4-6614/001; NSC-287208; 4-Chloro-α-methylphenethylamine; 1-(4-Chlorophenyl)propan-2-amine
Routes of
administration		Oral
Drug classSerotonin–norepinephrine–dopamine releasing agent; Serotonergic neurotoxin; Antidepressant; Stimulant
Legal status
Legal status
  • DE: NpSG (Industrial and scientific use only)
  • UK: Class A
Pharmacokinetic data
Duration of actionIM: 3–7 hours[1]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC9H12ClN
Molar mass169.65 g·mol−1
3D model (JSmol)
  (verify)

para-Chloroamphetamine (PCA), also known as 4-chloroamphetamine (4-CA), is a serotonin–norepinephrine–dopamine releasing agent (SNDRA) and serotonergic neurotoxin of the amphetamine family.[2][3][4][5] It is used in scientific research in the study of the serotonin system, as a serotonin releasing agent (SRA) at lower doses to produce serotonergic effects, and as a serotonergic neurotoxin at higher doses to produce long-lasting depletions of serotonin.[3][4]

PCA has also been clinically studied as an appetite suppressant and antidepressant, but findings of neurotoxicity in animals discouraged further evaluation.[6][1] It has also been encountered as a designer drug, although it never achieved popularity, again perhaps due to its neurotoxicity.[7][6]

Effects

PCA was studied clinically as an appetite suppressant and antidepressant and its effects in these studies were described.[6][1][8][9] It has been said to have only slight stimulant effects and to behave more like an antidepressant than a stimulant.[6] At doses of 80 to 90 mg daily, in 3 doses, it produced no significant acute psychoactive effects and produced few adverse effects.[6][1] However, sleep disturbances and nausea were mentioned.[6] No hallucinogenic effects have been reported.[2][1][10][11]

The profile of PCA is analogous to that of naphthylaminopropane (NAP; PAL-287), a highly potent and well-balanced SNDRA with only weak stimulant-like effects.[12] It is thought that concomitant robust serotonin release suppresses the stimulating and rewarding effects of dopamine release.[12][13]

Pharmacology

Monoamine releasing agent

PCA acts as a serotonin, norepinephrine, and dopamine releasing agent (SNDRA).[14][15][16] Its EC50 values for monoamine release are 28.3 nM for serotonin, 23.5 to 26.2 nM for norepinephrine, and 42.2 to 68.5 nM for dopamine in rat brain synaptosomes, making it a potent and well-balanced SNDRA.[14][15][17][18] It is also a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), with IC50 values of 490 nM for serotonin, 320 nM for norepinephrine, and 3,600 nM for dopamine in human embryonic kidney 293 (HEK293) cells.[19]

Short-term effects

In animals, doses of PCA of 0.5 to 5 mg/kg acutely produce a variety of behavioral and neurochemical effects thought to be due to serotonin release.[3][20][21] Consequent enhancement of serotonergic signaling, serotonergic effects like myoclonus, the serotonin behavioral syndrome, including tremor, rigidity, Straub tail, hindlimb abduction, lateral head weaving, and reciprocal forepaw treading, inhibition of startle response sensitization, suppression of sexual behavior in females, and the head-twitch response.[3][20] Non-behavioral or physiological effects include activation of the hypothalamic–pituitary–adrenal axis (HPA axis), increased prolactin secretion, and increased plasma renin activity.[3] PCA and other SRAs like MDMA and α-ethyltryptamine (αET) produce locomotor hyperactivity in animals and this is thought to be serotonin-dependent.[22] It is mimicked by serotonin 5-HT1B receptor activation.[22] However, PCA is also reported to produce amphetamine-like hyperactivity and stereotypy, as well as amphetamine-like enhancement of conditioned avoidance responding that is independent of serotonergic signaling.[20]

PCA does not show effects like those of the selective norepinephrine and dopamine releasing agent (NDRA) amphetamine in animals but instead fully substitutes for other serotonin releasing agents like (+)-MBDB and MMAI in rodent drug discrimination tests.[16] The findings with PCA are in contrast to those with para-fluoroamphetamine (PFA), which acts as a selective NDRA similarly to amphetamine,[23] fully substitutes for amphetamine in animals, and fails to substitute for (+)-MBDB or MMAI.[16] As touched on, PCA can robustly produce the head-twitch response, which is a behavioral proxy of psychedelic-like effects.[10][11][24][3] However, PCA does not seem to produce hallucinogenic effects in humans, and hence its activity in the head-twitch paradigm has been described as a false-positive for psychedelic effects.[10][11][25] The head-twitch response with PCA appears to be dependent on induction of serotonin release and not on direct serotonin receptor agonism by PCA, as it is blocked by destruction of presynaptic serotonergic nerve terminals or by serotonin synthesis inhibition.[10][24][26] Relatedly, PCA is said not to be a serotonin 5-HT2A receptor agonist (at concentrations up to 10,000 nM).[27] However, PCA might nonetheless act as a direct serotonin 5-HT2 receptor agonist at high doses, as head twitches induced by it are not blocked by serotonin synthesis inhibition at these doses.[26] Although PCA has been reported to produce the head-twitch response, a more modern study reported that it did not do so, at least unless the serotonin transporter (SERT) was artificially expressed in a population of medial prefrontal cortex (mPFC) serotonergic neurons that normally lack the SERT.[27]

While extracellular serotonin levels and serotonergic signaling are acutely increased by PCA, there is a concomitant depletion of serotonin stores.[3] The depletion includes a decrease in total serotonin content, 5-hydroxyindoleacetic acid (5-HIAA) content, and tryptophan hydroxylase activity.[3][20] The acute depletion of serotonin stores by PCA is likely due to inhibition of tryptophan hydroxylase.[5][20] How this occurs is unclear, as PCA does not inhibit tryptophan hydroxylase in vitro except at very high concentrations.[5][20] The initial serotonin depletion by lower doses of PCA are not permanent and can readily reverse after a few hours.[5] As such, low doses of PCA, such as 2 mg/kg, are regarded as non-neurotoxic.[21] The dopaminergic and noradrenergic systems are also substantially impacted by acute PCA.[20] However, dopamine and norepinephrine levels are only slightly changed.[20] In addition, the effects on the dopaminergic and noradrenergic systems are of relatively short duration and return to normal within 24 hours, analogously to the case of the serotonin system.[20] In line with the preceding neurochemical findings, tolerance to various of the behavioral effects of acute PCA has been found to develop.[20]

Due to its activity as a serotonin releasing agent, PCA is employed in scientific research to acutely enhance and study serotonin signaling.[4][22]

Long-term serotonergic neurotoxicity

At higher doses (e.g., 10 mg/kg) and for longer amounts of exposure, PCA produces extremely long-lasting depletion of serotonin and loss of serotonergic function that is considered to reflect serotonergic neurotoxicity.[3][20][21] This includes depletion of serotonin content, 5-HIAA content, serotonin turnover, tryptophan hydroxylase, serotonin reuptake capacity, and serotonin transporters for weeks or months.[3][5][20] As an example, brain serotonin continued to be reduced by 41% after 38 days.[3] In addition, many serotonin-containing nerve fibers become undetectable and appear to be lost.[3] There have also been observations of nerve degeneration in the days after PCA administration.[3][5][20] Different serotonergic areas and projections are differentially susceptible to the neurotoxicity of PCA, with the dorsal raphe nuclei more susceptible and the median raphe nuclei, raphe obscurus, raphe pallidus, dentate gyrus, hypothalamus, and spinal cord all resistant.[3][20] PCA is selective for serotonin, without causing depletion of norepinephrine or dopamine.[3][20]

There are behavioral consequences of the serotonergic neurotoxicity of PCA.[3][20] Affected animals are still quite normal in overall appearance.[3] However, hypoactivity, increased defecation in the open field test, and failed acquisition of shock avoidance in the Y-maze task are all apparent.[3] In addition, increased locomotion in response to the dopamine agonist apomorphine has been observed, which is consistent with findings that serotonin may inhibit certain aspects of dopamine signaling.[3] Failure of acquisition of a two-way conditioned avoidance response has been observed, and this could be completely prevented with the SRI zimelidine (see more on this below).[3] Various other changes and deficits have been seen as well.[3] The effects of the non-selective serotonin receptor agonist and serotonergic psychedelic 5-MeO-DMT have been found to be greatly potentiated following PCA, which may reflect receptor supersensitivity in an attempt at compensation for serotonin depletion.[3] Conversely, the behavioral and physiological serotonergic effects of acute low-dose PCA challenge are attenuated after high-dose neurotoxic PCA exposure, which may reflect reduced available serotonin stores for release.[3]

Mechanisms of neurotoxicity

Although the ultimate cause is cytotoxicity to serotonergic neurons, the mechanisms leading to the serotonergic neurotoxicity of PCA are unknown.[3][5][20] However, uptake of PCA into neurons by the serotonin transporter (SERT) appears to be required.[3][5][20] Serotonin reuptake inhibitors (SRIs) like fluoxetine can block both the acute short-term effects and the long-term serotonergic neurotoxicity of PCA.[3][5][20] In addition, they can be given 4 hours after PCA administration, when acute serotonin depletion has already occurred, and will still completely protect against the long-term neurotoxicity.[3] However, the SRI must be long-lasting; the short-acting SRI clomipramine, given before PCA, prevented acute serotonin depletion, but PCA outlasted clomipramine in the body, and the same degree of long-term neurotoxicity occurred as if clomipramine had not been administered.[3]

It has been theorized that a toxic metabolite of PCA may be formed and that this metabolite is responsible for its neurotoxicity.[5][20] However, no compelling evidence in support of this hypothesis has emerged.[3][5][20] Severe depletion of serotonin by the combination of para-chlorophenylalanine (PCPA) and reserpine substantially protects against the serotonergic neurotoxicity of PCA.[3] This might be due to serotonin forming neurotoxic metabolites, for instance 5,6-dihydroxytryptamine (5,6-DHT), in the context of PCA's actions.[3] Similarly to prophylactic serotonin depletion, α-methyl-p-tyrosine, which depletes dopamine, protects against the serotonergic neurotoxicity of PCA as well.[3] It thus appears that dopamine is involved in the neurotoxicity of PCA, which is notable as PCA is a potent dopamine releasing agent in addition to inducing the release of serotonin.[3]

It has been reported that direct intracerebroventricular injection of PCA into the brain, in contrast to peripheral administration, failed to produce serotonergic neurotoxicity.[3] This was the case even with continuous infusion for two days.[3] This seems like it may lend credence to the toxic metabolite theory of PCA neurotoxicity, as a peripherally formed metabolite of PCA might be required for neurotoxicity to occur.[3] However, no toxic metabolite has still yet been identified and no other support for the hypothesis has surfaced.[3] Inhibiting the metabolism of PCA does not reduce tryptophan hydroxylase inactivation, suggesting that a metabolite is not responsible for this effect.[20]

There are species differences in the neurotoxicity of PCA between rats and mice, which may help to shed light on the underlying mechanisms.[20]

Structure–activity relationships of neurotoxicity

The drug is the most potent serotonergic neurotoxin of a series of amphetamines.[3][5] In terms of structure–activity relationships, the α-methyl group appears to be essential for the neurotoxicity, and the α-ethyl analogue is less potent as a neurotoxin.[3][5] Other side chain homologues with shorter or longer chains were less potent or inactive.[3][5] Moving the chloro substituent to other positions on the phenyl ring, as in ortho-chloroamphetamine (OCA) and meta-chloroamphetamine (MCA), resulted in no significant serotonergic depletion, in contrast to the marked depletion with PCA.[3][5] However, this was found to be due to rapid metabolism in the case of MCA, and inhibiting its metabolism resulted in potent neurotoxicity as with PCA.[5] Conversely, OCA still does not produce apparent neurotoxicity.[5]

para-Bromoamphetamine (PBA) and para-bromomethamphetamine (PBMA) show similar serotonergic neurotoxicity to PCA and PCMA.[5] Conversely, para-fluoroamphetamine decreases serotonin levels but its effects appear to be much less persistent than those of PCA.[5] Other 4-substituted amphetamines have reduced neurotoxicity (4-trifluoromethylamphetamine, 4-phenoxyamphetamine) or are inactive (4-methylamphetamine, para-methoxyamphetamine (PMA)) in terms of serotonin depletion.[5] Fenfluramine and norfenfluramine, which are 3-trifluoromethylamphetamines, produce very long-lasting serotonergic neurotoxicity similarly to PCA but are slightly less active.[5]

The closely related N-methylated derivative, para-chloromethamphetamine (PCMA), which is rapidly and extensively metabolized to para-chloroamphetamine in vivo, has neurotoxic properties as well, and is only slightly less potent than PCA in this regard.[3][5] Other N-alkylated analogues of PCA also metabolize at least in part into PCA and produce serotonergic neurotoxicity.[3][5] However, they show reduced activity, which may be due to their extent of conversion into PCA being reduced.[5]

In contrast to PCA, the phentermine (i.e., α-methylated) analogue of PCA, chlorphentermine, which acts as a highly selective SRA,[28][29] does not appear to produce serotonergic neurotoxicity.[30]

Rigid analogues of PCA, like 6-chloro-2-aminotetralin (6-CAT), have also been assessed.[5] 6-CAT depletes serotonin similarly to PCA, but its effects are smaller and shorter-lasting.[5] Another analogue, Org 6582, in which a third ring structure has been added, is a selective serotonin reuptake inhibitor (SSRI) and no longer shows the serotonergic neurotoxicity of PCA and 6-CAT.[5]

Use as a neurotoxin in scientific research

PCA is useful and widely employed as a serotonergic neurotoxin in scientific research.[3][4] A variety of scientific findings have been made and published through employment of PCA.[3] The drug is advantageous over other serotonergic neurotoxins like 5,6-dihydroxytryptamine (5,6-DHT) and 5,7-dihydroxytryptamine (5,7-DHT) in that it is active by systemic administration.[3] Conversely, 5,6-DHT and 5,7-DHT do not cross the blood–brain barrier and must be administered directly into the brain.[3] PCA also produces a different anatomical pattern of serotonergic neurotoxicity than 5,6-DHT and 5,7-DHT, which can be useful as well if there is a need to study different serotonergic areas or pathways.[3]

Other actions

PCA has been found to act as a relatively potent monoamine oxidase A (MAO-A) inhibitor, with an IC50 of 1,900 to 4,000 nM.[31]

PCA has been reported to act as an agonist of the rat trace amine-associated receptor (TAAR1).[32][33] Conversely, it is not a significant agonist of the human TAAR1.[34] The drug also appears to be inactive as an agonist of the mouse TAAR1.[34] TAAR1 agonism has been implicated in modulating the effects of monoamine releasing agents (MRAs).[35] In contrast to PCA, the MRA MDMA is a potent agonist of the mouse TAAR1.[34][36] MDMA-induced in-vivo brain serotonin and dopamine release and hyperlocomotion are augmented in TAAR1 knockout mice relative to normal mice, whereas the in-vivo brain serotonin and dopamine release of PCA are not different between normal mice and TAAR1 knockout mice.[34][37] In the same study, the TAAR1 agonist o-phenyl-3-iodotyramine (o-PIT) blunted the dopamine and serotonin release of PCA in mouse synaptosomes in vitro, an effect that was absent in synaptosomes from TAAR1 knockout mice.[34][37] These findings led to conclusions that TAAR1 agonism by MDMA but not PCA auto-inhibits and constrains its own effects in rodents.[37][34] Unlike in rodents however, MDMA is not a significant TAAR1 agonist in humans.[36][38][39][40]

Chemistry

PCA, also known as 4-chloroamphetamine, is a phenethylamine and amphetamine derivative.[1][5]

Analogues of PCA include para-chloromethamphetamine (PCMA/4-CMA), para-bromoamphetamine (PBA/4-BA), para-fluoroamphetamine (PFA/4-FA), para-iodoamphetamine (PIA/4-IA), 4-methylamphetamine (4-MA), meta-chloroamphetamine (MCA/4-CA), ortho-chloroamphetamine (OCA/2-CA), 3,4-dichloroamphetamine (3,4-DCA), 2,4-dichloroamphetamine (2,4-DCA), chlorphentermine, 4-chloromethcathinone (4-CMC; clephedrone), 4-chlorophenylisobutylamine (4-CAB; AEPCA), 6-chloro-2-aminotetralin (6-CAT), 5-iodo-2-aminoindane (5-IAI), and Org 6582, among others.[2][3][5][1]

History

PCA was first synthesized by 1936[1] and was first developed for potential medical use in the 1960s.[1][41][42][8][9]

Society and culture

China

As of October 2015, 4-CA is a controlled substance in China.[43]

United States

PCA is not a scheduled compound in the United States.[2]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Shulgin, Alexander T. (1978). "Psychotomimetic Drugs: Structure-Activity Relationships". Stimulants. Boston, MA: Springer US. pp. 243–333. doi:10.1007/978-1-4757-0510-2_6. ISBN 978-1-4757-0512-6. https://bitnest.netfirms.com/external/10.1007/978-1-4757-0510-2_6. "Considerable clinical application of 4-CA has been made, and it has been found effective as an antidepressant when used chronically at levels of 75 mg/day (van Praag et al., 1971; van Praag and Korf, 1976). There are very few side effects noted and the drug is tolerated very well. However, indications of raphe-nucleus degeneration (Yunger et al., 1974) and related neurotoxicity (Harvey and McMaster, 1976) in experimental animals have discouraged further clinical study. [...] There were no reports from the clinical studies of 4-CA that suggested any psychotomimetic action." 
  2. ↑ 2.0 2.1 2.2 2.3 The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. 1. Berkeley: Transform Press. 2011. ISBN 978-0-9630096-3-0. 
  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 3.25 3.26 3.27 3.28 3.29 3.30 3.31 3.32 3.33 3.34 3.35 3.36 3.37 3.38 3.39 3.40 3.41 3.42 3.43 3.44 3.45 3.46 3.47 3.48 "Effects of p-chloroamphetamine on brain serotonin neurons". Neurochem Res 17 (5): 449–456. May 1992. doi:10.1007/BF00969891. PMID 1528354. 
  4. ↑ 4.0 4.1 4.2 4.3 "Biochemical pharmacology of the serotonin system". Adv Neurol 43: 469–480. 1986. PMID 2936068. 
  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 "Structure-activity relationships among the halogenated amphetamines". Ann N Y Acad Sci 305 (1): 147–159. June 1978. doi:10.1111/j.1749-6632.1978.tb31518.x. PMID 152079. Bibcode: 1978NYASA.305..147F. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "Identification and characterization of 4-chloromethamphetamine (4-CMA) in seized ecstacy - a risk to public health". Forensic Sci Int 288: 173–180. July 2018. doi:10.1016/j.forsciint.2018.04.023. PMID 29753935. "Psychoactive effects of 4-CMA and 4-CA were evaluated in humans while researching both compounds as antidepressants. In the dosages used (80-90 mg daily, in 3 doses), no significant acute psychoactive effects were noticed; adverse effects were also low, although an effect on sleep and nausea was mentioned [7].". 
  7. ↑ "Designer drugs: mechanism of action and adverse effects". Arch Toxicol 94 (4): 1085–1133. April 2020. doi:10.1007/s00204-020-02693-7. PMID 32249347. Bibcode: 2020ArTox..94.1085L. "Compared with amphetamine, an increase in serotonergic toxicity has been reported for the para-chlorinated derivative 4-chloroamphetamine, likely explained by highly potent serotonergic activity coupled with considerably potent dopaminergic activity (Colado et al. 1993; Fuller 1992; Johnson et al. 1990; Luethi et al. 2019b; Miller et al. 1986). However, unlike other halogenated stimulants, such as 4-fluoroamphetamine, 4-chloroamphetamine never achieved popularity as a designer drug, possibly because of its well-documented neurotoxicity.". 
  8. ↑ 8.0 8.1 "A comparative study of the therapeutic effects of sone 4-chlorinated amphetamine derivatives in depressive patients". Psychopharmacologia 20 (1): 66–76. 1971. doi:10.1007/BF00404060. PMID 5565748. 
  9. ↑ 9.0 9.1 "4-Chloramphetamines. Chance and trend in the development of new antidepressants". J Clin Pharmacol New Drugs 13 (1): 3–14. January 1973. doi:10.1002/j.1552-4604.1973.tb00063.x. PMID 4566121. 
  10. ↑ 10.0 10.1 10.2 10.3 "Effect of Hallucinogens on Unconditioned Behavior". Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences. 36. Berlin, Heidelberg: Springer Berlin Heidelberg. 2018. pp. 159–199. doi:10.1007/7854_2016_466. ISBN 978-3-662-55878-2. "Amphetamine and methamphetamine, which act primarily by increasing carrier-mediated release of dopamine and norepinephrine, do not provoke head twitches (Corne and Pickering 1967; Silva and Calil 1975; Yamamoto and Ueki 1975; Jacobs et al. 1976; Bedard and Pycock 1977; Halberstadt and Geyer 2013). By contrast, the 5-HT releasing drugs fenfluramine and p-chloroamphetamine (PCA) do produce a robust HTR (Singleton and Marsden 1981; Darmani 1998a). Fenfluramine and PCA are thought to act indirectly, by increasing carrier-mediated release of 5-HT, because the response can be blocked by inhibition of the 5-HT transporter (Balsara et al. 1986; Darmani 1998a) or by depletion of 5-HT (Singleton and Marsden 1981; Balsara et al. 1986). [...] Because indirect 5-HT agonists such as fenfluramine, PCA, and 5-HTP are not hallucinogenic (Van Praag et al. 1971; Brauer et al. 1996; Turner et al. 2006), their effects on HTR can potentially be classified as false-positive responses." 
  11. ↑ 11.0 11.1 11.2 "Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species". Neuropharmacology 167. May 2020. doi:10.1016/j.neuropharm.2019.107933. PMID 31917152. "Indirect 5-HT2A agonists such as fenfluramine, p-chloroamphetamine (PCA), and 5-hydroxytryptophan (5-HTP) induce head twitches in rodents (Corne et al. 1963; Singleton and Marsden 1981; Darmani 1998) but do not act as hallucinogens in humans (van Praag et al. 1971; Brauer et al. 1996; Turner et al. 2006), However, overdoses of compounds that increase serotonin (5-HT) release can result in 5-HT syndrome, which sometimes includes hallucinations (Birmes et al. 2003; Evans and Sebastian 2007).". 
  12. ↑ 12.0 12.1 "Dual dopamine/serotonin releasers: potential treatment agents for stimulant addiction". Exp Clin Psychopharmacol 16 (6): 458–474. December 2008. doi:10.1037/a0014103. PMID 19086767. 
  13. ↑ "Balance between dopamine and serotonin release modulates behavioral effects of amphetamine-type drugs". Ann N Y Acad Sci 1074 (1): 245–260. August 2006. doi:10.1196/annals.1369.064. PMID 17105921. Bibcode: 2006NYASA1074..245R. 
  14. ↑ 14.0 14.1 Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines. 22 May 2012. https://scholarworks.uno.edu/td/1436/. Retrieved 4 November 2024. 
  15. ↑ 15.0 15.1 "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. 
  16. ↑ 16.0 16.1 16.2 "Psychostimulant-like effects of p-fluoroamphetamine in the rat". European Journal of Pharmacology 287 (2): 105–113. December 1995. doi:10.1016/0014-2999(95)00478-5. PMID 8749023. 
  17. ↑ "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. 
  18. ↑ "In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones". 2022. 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. [...]" 
  19. ↑ "Para-Halogenation Affects Monoamine Transporter Inhibition Properties and Hepatocellular Toxicity of Amphetamines and Methcathinones". Front Pharmacol 10. 2019. doi:10.3389/fphar.2019.00438. PMID 31068823. PMC 6491784. https://www.researchgate.net/publication/332605664. 
  20. ↑ 20.00 20.01 20.02 20.03 20.04 20.05 20.06 20.07 20.08 20.09 20.10 20.11 20.12 20.13 20.14 20.15 20.16 20.17 20.18 20.19 20.20 20.21 20.22 "Immediate and long-term effects of p-chloroamphetamine on brain amines". Ann N Y Acad Sci 305 (1): 208–221. June 1978. doi:10.1111/j.1749-6632.1978.tb31525.x. PMID 360935. Bibcode: 1978NYASA.305..208S. 
  21. ↑ 21.0 21.1 21.2 "Studies on the mechanism of p-chloroamphetamine neurotoxicity". Biochem Pharmacol 52 (8): 1271–1277. October 1996. doi:10.1016/0006-2952(96)00482-0. PMID 8937435. 
  22. ↑ 22.0 22.1 22.2 "Serotonergic functions in arousal and motor activity". Behav Brain Res 73 (1–2): 31–35. 1996. doi:10.1016/0166-4328(96)00065-4. PMID 8788473. 
  23. ↑ "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. 
  24. ↑ 24.0 24.1 "Effects of 5,7-dihydroxytryptamine and 6-hydroxydopamine on head-twitch response induced by serotonin, p-chloroamphetamine, and tryptamine in mice". Psychopharmacology (Berl) 95 (1): 124–131. 1988. doi:10.1007/BF00212780. PMID 3133691. "Head-twitch response (HTR) in mice was induced by intracerebroventricular injection of tryptamine (TRA) as well as serotonin (5-HT) and p-chloroamphetamine (PCA). Pretreatment with 5,7-dihydroxytryptamine enhanced both the 5-HT-induced and the TRA-induced HTR. The PCA-induced HTR, however, was attenuated by the drug. On the other hand, pretreatment with 6-hydroxydopamine did not alter the 5-HT response but enhanced both the PCA- and the TRA-induced response. These results suggest that 5-HT may directly stimulate the post-synaptic receptors, while the PCA response may be based on the release of endogenous 5-HT.". 
  25. ↑ "Molecular and Medical Aspects of Psychedelics". Int J Mol Sci 25 (1): 241. December 2023. doi:10.3390/ijms25010241. PMID 38203411. "While some false positives have been identified, such as fenfluramine, p-chloroamphetamine, and 5-hydroxytryptophan, the test predominantly exhibits specificity for 5-HT2A receptor agonists [15].". 
  26. ↑ 26.0 26.1 "Substituted amphetamine derivatives. II. Behavioural effects in mice related to monoaminergic neurones". Acta Pharmacol Toxicol (Copenh) 41 (4): 353–368. October 1977. doi:10.1111/j.1600-0773.1977.tb02674.x. PMID 303437. 
  27. ↑ 27.0 27.1 "Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors". Science 379 (6633): 700–706. February 2023. doi:10.1126/science.adf0435. PMID 36795823. Bibcode: 2023Sci...379..700V. "[...] both groups were administered (±)-para-chloroamphetamine (PCA, 5 mg/kg, IP)—a selective serotonin-releasing agent (43). [...] Importantly, PCA is not a 5-HT2AR agonist (fig. S10A), [...] and does not induce a HTR in wild type mice (fig. S10C). [...] In addition to promoting psychedelic-induced structural neuroplasticity, the intracellular population of 5-HT2ARs might also contribute to the hallucinogenic effects of psychedelics. When we administered a serotonin-releasing agent to wild type mice, we did not observe a HTR. However, the same drug was able to induce a HTR in mice expressing SERT on cortical neurons of the mPFC—a brain region known to be essential for the HTR (49).". 
  28. ↑ "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. 
  29. ↑ "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. 
  30. ↑ "Chlorinated amphetamines: drugs or toxins". Clinical Pharmacology of Serotonin. Monographs in Neural Sciences. 3. 1976. pp. 109–114. doi:10.1159/000399342. ISBN 978-3-8055-2328-8. "A methylated analogue of p-chloroamphetamine is chlorphentermine (fig. 1). This compound is marketed as an appetite suppressant Pre-Sate® and it seemed of interest to reevaluate the effects of this compound on the serotonergic system. One day following the administration of 20 mg/kg to rats there appeared to be little loss of tryptophan hydroxylase in any of the brain regions; e.g., mesencephalic tegmentum 124 %, mesencephalic tectum 95.7 % and striatum 103.5 %, of control values. While this preliminary experiment would suggest that chlorphentermine is not neurotoxic, it would seem in view of the similarity of its structure to p-chloroamphetamine that considerably more detailed experiments should be done to evaluate the long-term effects of this drug and its potential neurotoxicity." 
  31. ↑ "Amphetamine Derivatives as Monoamine Oxidase Inhibitors". Front Pharmacol 10. 2019. doi:10.3389/fphar.2019.01590. PMID 32038257. 
  32. ↑ "TAAR1 and Psychostimulant Addiction". Cell Mol Neurobiol 40 (2): 229–238. March 2020. doi:10.1007/s10571-020-00792-8. PMID 31974906. "Amphetamine-like compounds, including amphetamine (AMPH), methamphetamine (METH), MDMA, 4-OH-amphetamine, 4-Cl-amphetamine could induce cAMP accumulation in the HEK-293 cells expressing [rat] TAAR1, indicating that amphetamines are potent agonists of TAAR1 (Bunzow et al. 2001; Miller et al. 2005).". 
  33. ↑ "Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor". Mol Pharmacol 60 (6): 1181–1188. December 2001. doi:10.1124/mol.60.6.1181. PMID 11723224. 
  34. ↑ 34.0 34.1 34.2 34.3 34.4 34.5 "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. 
  35. ↑ "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. 
  36. ↑ 36.0 36.1 "Trace Amines and Their Receptors". Pharmacol Rev 70 (3): 549–620. July 2018. doi:10.1124/pr.117.015305. PMID 29941461. 
  37. ↑ 37.0 37.1 37.2 "Striatal Tyrosine Hydroxylase Is Stimulated via TAAR1 by 3-Iodothyronamine, But Not by Tyramine or β-Phenylethylamine". Front Pharmacol 9. 2018. doi:10.3389/fphar.2018.00166. PMID 29545750. "Di Cara et al. (2011) showed that TAAR1 decreases the amplitude of Methylenedioxymethamphetamine (MDMA) induced dopamine release both in ventral and dorsal striatum. In the same study it was observed that the TAAR1 agonist, o-phenyl-3-iodotyramine (o-PIT) blunted the para-chloroamphetamine (PCA) induced dopamine release in both structures (Di Cara et al., 2011).". 
  38. ↑ "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. 
  39. ↑ "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. 
  40. ↑ "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". 
  41. ↑ "Anorexigenic Agents: Aromatic Substituted 1-Phenyl-2-propylamines". J Med Chem 6 (5): 519–524. September 1963. doi:10.1021/jm00341a011. PMID 14173573. 
  42. ↑ "Lowering of Brain Serotonin Level By Chloroamphetamines". Biochem Pharmacol 14 (4): 483–488. April 1965. doi:10.1016/0006-2952(65)90221-2. PMID 14322972. 
  43. ↑ "关于印发《非药用类麻醉药品和精神药品列管办法》的通知" (in zh). China Food and Drug Administration. 27 September 2015. http://www.sfda.gov.cn/WS01/CL0056/130753.html. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:Para-Chloroamphetamine&oldid=4036089"