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para-Chloroamphetamine

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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 actionIMTooltip Intramuscular Injection: 3–7 hours[1]
Identifiers
  • 1-(4-Chlorophenyl)propan-2-amine
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC9H12ClN
Molar mass169.65 g·mol−1
3D model (JSmol)
  • Clc1ccc(cc1)CC(N)C
  • InChI=1S/C9H12ClN/c1-7(11)6-8-2-4-9(10)5-3-8/h2-5,7H,6,11H2,1H3 checkY
  • Key:WWPITPSIWMXDPE-UHFFFAOYSA-N checkY
  (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

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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 psychostimulant 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

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Monoamine releasing agent

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PCA acts as a serotonin, norepinephrine, and dopamine releasing agent (SNDRA).[14][15][16] Its EC50Tooltip half-maximal effective concentration 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, making it a potent and well-balanced SNDRA.[14][15][17][18]

Short-term effects

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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][19][20] 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][19] 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.[21] It is mimicked by serotonin 5-HT1B receptor activation.[21] 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.[19]

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,[22] 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][23][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][24] 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][23][25] Relatedly, PCA is said not to be a serotonin 5-HT2A receptor agonist (at concentrations up to 10,000 nM).[26] 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.[25] 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.[26]

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][19] The acute depletion of serotonin stores by PCA is likely due to inhibition of tryptophan hydroxylase.[5][19] How this occurs is unclear, as PCA does not inhibit tryptophan hydroxylase in vitro except at very high concentrations.[5][19] 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.[20] The dopaminergic and noradrenergic systems are also substantially impacted by acute PCA.[19] However, dopamine and norepinephrine levels are only slightly changed.[19] 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.[19] In line with the preceding neurochemical findings, tolerance to various of the behavioral effects of acute PCA has been found to develop.[19]

Due to its activity as a serotonin releasing agent, PCA is employed in scientific research to acutely enhance and study serotonin signaling.[4][21]

Long-term serotonergic neurotoxicity

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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][19][20] 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][19] 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][19] 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][19] PCA is selective for serotonin, without causing depletion of norepinephrine or dopamine.[3][19]

There are behavioral consequences of the serotonergic neurotoxicity of PCA.[3][19] 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
[edit]

Although the ultimate cause is cytotoxicity to serotonergic neurons, the mechanisms leading to the serotonergic neurotoxicity of PCA are unknown.[3][5][19] However, uptake of PCA into neurons by the serotonin transporter (SERT) appears to be required.[3][5][19] Serotonin reuptake inhibitors (SRIs) like fluoxetine can block both the acute short-term effects and the long-term serotonergic neurotoxicity of PCA.[3][5][19] 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][19] However, no compelling evidence in support of this hypothesis has emerged.[3][5][19] 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.[19]

There are species differences in the neurotoxicity of PCA between rats and mice, which may help to shed light on the underlying mechanisms.[19]

Structure–activity relationships of neurotoxicity
[edit]

The drug is the most potent serotonergic neurotoxin of a series of amphetamines.[3][5] In terms of structure–activity relationships, the α-methyl croup 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,[27][28] does not appear to produce serotonergic neurotoxicity.[29]

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 and no longer shows the serotonergic neurotoxicity of PCA and 6-CAT.[5]

Use as a neurotoxin in scientific research
[edit]

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]

Monoamine oxidase inhibitor

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PCA has been found to act as a monoamine oxidase A (MAO-A) inhibitor, with an IC50Tooltip half-maximal inhibitory concentration of 1,900 to 4,000 nM.[30]

Chemistry

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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

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PCA was first synthesized by 1936[1] and was first developed for potential medical use in the 1960s.[1][31][32][8][9]

Society and culture

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[edit]

China

[edit]

As of October 2015, 4-CA is a controlled substance in China.[33]

United States

[edit]

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

References

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  1. ^ a b c d e f g h i Shulgin AT (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. 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. ^ a b c d Shulgin A, Manning T, Daley PF (2011). The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. Vol. 1. Berkeley: Transform Press. ISBN 978-0-9630096-3-0.
  3. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw Fuller RW (May 1992). "Effects of p-chloroamphetamine on brain serotonin neurons". Neurochem Res. 17 (5): 449–456. doi:10.1007/BF00969891. PMID 1528354.
  4. ^ a b c d Fuller RW (1986). "Biochemical pharmacology of the serotonin system". Adv Neurol. 43: 469–480. PMID 2936068.
  5. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac Fuller RW (June 1978). "Structure-activity relationships among the halogenated amphetamines". Ann N Y Acad Sci. 305: 147–159. doi:10.1111/j.1749-6632.1978.tb31518.x. PMID 152079.
  6. ^ a b c d e f Blanckaert P, Vanquekelberghe S, Coopman V, Risseeuw MD, Van Calenbergh S, Cordonnier J (July 2018). "Identification and characterization of 4-chloromethamphetamine (4-CMA) in seized ecstacy - a risk to public health". Forensic Sci Int. 288: 173–180. doi:10.1016/j.forsciint.2018.04.023. hdl:1854/LU-8569680. 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. ^ Luethi D, Liechti ME (April 2020). "Designer drugs: mechanism of action and adverse effects". Arch Toxicol. 94 (4): 1085–1133. doi:10.1007/s00204-020-02693-7. PMC 7225206. PMID 32249347. 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. ^ a b van Praag HM, Schut T, Bosma E, van den Bergh R (1971). "A comparative study of the therapeutic effects of sone 4-chlorinated amphetamine derivatives in depressive patients". Psychopharmacologia. 20 (1): 66–76. doi:10.1007/BF00404060. PMID 5565748.
  9. ^ a b van Praag HM, Korf J (January 1973). "4-Chloramphetamines. Chance and trend in the development of new antidepressants". J Clin Pharmacol New Drugs. 13 (1): 3–14. doi:10.1002/j.1552-4604.1973.tb00063.x. PMID 4566121.
  10. ^ a b c d Halberstadt AL, Geyer MA (2018). "Effect of Hallucinogens on Unconditioned Behavior". In Halberstadt AL, Vollenweider FX, Nichols DE (eds.). Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences. Vol. 36. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 159–199. doi:10.1007/7854_2016_466. ISBN 978-3-662-55878-2. PMC 5787039. PMID 28224459. 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. ^ a b c Halberstadt AL, Chatha M, Klein AK, Wallach J, Brandt SD (May 2020). "Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species". Neuropharmacology. 167: 107933. doi:10.1016/j.neuropharm.2019.107933. PMC 9191653. 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. ^ a b Rothman RB, Blough BE, Baumann MH (December 2008). "Dual dopamine/serotonin releasers: potential treatment agents for stimulant addiction". Exp Clin Psychopharmacol. 16 (6): 458–474. doi:10.1037/a0014103. PMC 2683464. PMID 19086767.
  13. ^ Rothman RB, Baumann MH (August 2006). "Balance between dopamine and serotonin release modulates behavioral effects of amphetamine-type drugs". Ann N Y Acad Sci. 1074: 245–260. doi:10.1196/annals.1369.064. PMID 17105921.
  14. ^ a b Forsyth AN (22 May 2012). "Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines". ScholarWorks@UNO. Retrieved 4 November 2024.
  15. ^ a b Blough B (July 2008). "Dopamine-releasing agents" (PDF). In Trudell ML, Izenwasser S (eds.). Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. OL 18589888W.
  16. ^ a b c Marona-Lewicka D, Rhee GS, Sprague JE, Nichols DE (December 1995). "Psychostimulant-like effects of p-fluoroamphetamine in the rat". European Journal of Pharmacology. 287 (2): 105–113. doi:10.1016/0014-2999(95)00478-5. PMID 8749023.
  17. ^ Fitzgerald LR, Gannon BM, Walther D, Landavazo A, Hiranita T, Blough BE, et al. (March 2024). "Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones". Neuropharmacology. 245: 109827. doi:10.1016/j.neuropharm.2023.109827. PMC 10842458. PMID 38154512.
  18. ^ Nicole L (2022). "In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones". ProQuest. Retrieved 5 December 2024. 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. ^ a b c d e f g h i j k l m n o p q r s t u v w Sanders-Bush E, Steranka LR (June 1978). "Immediate and long-term effects of p-chloroamphetamine on brain amines". Ann N Y Acad Sci. 305: 208–221. doi:10.1111/j.1749-6632.1978.tb31525.x. PMID 360935.
  20. ^ a b c Sprague JE, Johnson MP, Schmidt CJ, Nichols DE (October 1996). "Studies on the mechanism of p-chloroamphetamine neurotoxicity". Biochem Pharmacol. 52 (8): 1271–1277. doi:10.1016/0006-2952(96)00482-0. PMID 8937435.
  21. ^ a b c Geyer MA (1996). "Serotonergic functions in arousal and motor activity". Behav Brain Res. 73 (1–2): 31–35. doi:10.1016/0166-4328(96)00065-4. PMID 8788473.
  22. ^ Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL (May 2005). "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. doi:10.1124/jpet.104.080101. PMID 15677348. S2CID 12135483.
  23. ^ a b Orikasa S, Sloley BD (1988). "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. 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.
  24. ^ Wojtas A, Gołembiowska K (December 2023). "Molecular and Medical Aspects of Psychedelics". Int J Mol Sci. 25 (1): 241. doi:10.3390/ijms25010241. PMC 10778977. 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].
  25. ^ a b Ogren SO, Ross SB (October 1977). "Substituted amphetamine derivatives. II. Behavioural effects in mice related to monoaminergic neurones". Acta Pharmacol Toxicol (Copenh). 41 (4): 353–368. doi:10.1111/j.1600-0773.1977.tb02674.x. PMID 303437.
  26. ^ a b Vargas MV, Dunlap LE, Dong C, Carter SJ, Tombari RJ, Jami SA, et al. (February 2023). "Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors". Science. 379 (6633): 700–706. doi:10.1126/science.adf0435. PMC 10108900. PMID 36795823. [...] 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).
  27. ^ Rothman RB, Baumann MH (July 2002). "Therapeutic and adverse actions of serotonin transporter substrates". Pharmacology & Therapeutics. 95 (1): 73–88. doi:10.1016/s0163-7258(02)00234-6. PMID 12163129.
  28. ^ Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry. 6 (17): 1845–1859. doi:10.2174/156802606778249766. PMID 17017961.
  29. ^ Lovenberg W, Walker MN, Baumgarten HG (1976). "Chlorinated amphetamines: drugs or toxins". Clinical Pharmacology of Serotonin. Monographs in Neural Sciences. Vol. 3. pp. 109–114. doi:10.1159/000399342. ISBN 978-3-8055-2328-8. PMID 790166. 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.
  30. ^ Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK (2019). "Amphetamine Derivatives as Monoamine Oxidase Inhibitors". Front Pharmacol. 10: 1590. doi:10.3389/fphar.2019.01590. PMC 6989591. PMID 32038257.
  31. ^ Holland GF, Buck CJ, Weissman A (September 1963). "Anorexigenic Agents: Aromatic Substituted 1-Phenyl-2-propylamines". J Med Chem. 6 (5): 519–524. doi:10.1021/jm00341a011. PMID 14173573.
  32. ^ Fuller RW, Hines CW, Mills J (April 1965). "Lowering of Brain Serotonin Level By Chloroamphetamines". Biochem Pharmacol. 14 (4): 483–488. doi:10.1016/0006-2952(65)90221-2. PMID 14322972.
  33. ^ "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 Chinese). China Food and Drug Administration. 27 September 2015. Archived from the original on 1 October 2015. Retrieved 1 October 2015.
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