3-Chloroamphetamine

{{Short description|Serotonergic neurotoxin}}

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| image = 3-Chloroamphetamine.svg

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| class = Psychostimulant; Serotonergic neurotoxin

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| CAS_number = 32560-59-1

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| PubChem = 20027470

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| ChemSpiderID = 14677942

| UNII = 8V8DE89CJE

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| ChEMBL = 149022

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| synonyms = 3-CA; meta-Chloroamphetamine; m-Chloroamphetamine; MCA; PAL-304; PAL304

| IUPAC_name = 1-(3-chlorophenyl)propan-2-amine

| C=9 | H=12 | Cl=1 | N=1

| SMILES = CC(CC1=CC(=CC=C1)Cl)N

| StdInChI = 1S/C9H12ClN/c1-7(11)5-8-3-2-4-9(10)6-8/h2-4,6-7H,5,11H2,1H3

| StdInChIKey = ORWQJKNRYUIFJU-UHFFFAOYSA-N

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3-Chloroamphetamine (3-CA; code name PAL-304), also known as meta-chloroamphetamine (MCA), is a psychostimulant of the amphetamine family and a serotonergic neurotoxin related to para-chloroamphetamine (PCA; 4-chloroamphetamine).{{cite book | vauthors = Biel JH, Bopp BA | title=Stimulants | chapter=Amphetamines: Structure-Activity Relationships | publisher=Springer US | publication-place=Boston, MA | date=1978 | isbn=978-1-4757-0512-6 | doi=10.1007/978-1-4757-0510-2_1 | page=1–39 | quote = The position of the chloro substituent also markedly affects the activity of the compounds (Table 6). The effect of the meta derivative was approximately equivalent to that of the para derivative but only after inhibition of para-hydroxylation, while the ortho-substituted compound actually slightly raised rather than lowered the serotonin levels (Fuller and Molloy, 1974). }}{{cite journal | vauthors = Coppola M, Mondola R | title = 4-methylamphetamine (4-MA): chemistry, pharmacology and toxicology of a new potential recreational drug | journal = Mini Reviews in Medicinal Chemistry | volume = 13 | issue = 14 | pages = 2097–2101 | date = December 2013 | pmid = 24195663 | doi = 10.2174/13895575113136660106 | quote = [...] was less potent than amphetamine, 3-chloroamphetamine and 4-chloroamphetamine in inducing motor stimulation [31]. [...] }}{{cite book | vauthors = Lapoint J, Welker KL | chapter=Synthetic amphetamine derivatives, benzofurans, and benzodifurans | veditors = Dargan P, Wood D | title=Novel Psychoactive Substances | publisher=Elsevier | year=2022 | isbn=978-0-12-818788-3 | doi=10.1016/b978-0-12-818788-3.00007-3 | pages=247–278 | quote=[...] amphetamine analogue required to increase motor activity by 200 percent was 38 μmol/kg for 4-MA, 16 μmol/kg for amphetamine and 24 μmol/kg for both 2- and 3-chloroamphetamine.}}{{cite journal | vauthors = Fuller RW, Baker JC | title = Long-lasting reduction of brain 5-hydroxytryptamine concentration by 3-chloramphetamine and 4-chloroamphetamine in iprindole-treated rats | journal = The Journal of Pharmacy and Pharmacology | volume = 26 | issue = 11 | pages = 912–914 | date = November 1974 | pmid = 4156568 | doi = 10.1111/j.2042-7158.1974.tb09206.x }}

The drug is a potent serotonin–norepinephrine–dopamine releasing agent (SNDRA).{{cite web | last=Forsyth | first=Andrea N | title=Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines | website=ScholarWorks@UNO | date=22 May 2012 | url=https://scholarworks.uno.edu/td/1436/ | access-date=4 November 2024}}{{cite book | vauthors = Blough B | chapter = Dopamine-releasing agents | veditors = Trudell ML, Izenwasser S | title = Dopamine Transporters: Chemistry, Biology and Pharmacology | pages = 305–320 | date = July 2008 | isbn = 978-0-470-11790-3 | oclc = 181862653 | ol = OL18589888W | publisher = Wiley | location = Hoboken [NJ] | doi = | url = https://books.google.com/books?id=QCagLAAACAAJ | chapter-url = https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf }}{{cite journal | vauthors = Ross SB, Ogren SO, Renyi AL | title = Substituted amphetamine derivatives. I. Effect on uptake and release of biogenic monoamines and on monoamine oxidase in the mouse brain | journal = Acta Pharmacol Toxicol (Copenh) | volume = 41 | issue = 4 | pages = 337–352 | date = October 1977 | pmid = 579062 | doi = 10.1111/j.1600-0773.1977.tb02673.x | url = }} Its {{Abbrlink|EC₅₀|half-maximal effective concentration}} values for induction of monoamine release are 9.4{{nbsp}}nM for norepinephrine, 11.8{{nbsp}}nM for dopamine, and 120{{nbsp}}nM for serotonin. Hence, 3-CA shows around 10-fold preference for induction of catecholamine release over induction of serotonin release.{{cite journal | vauthors = Blough BE, Landavazo A, Partilla JS, Baumann MH, Decker AM, Page KM, Rothman RB | title = Hybrid dopamine uptake blocker-serotonin releaser ligands: a new twist on transporter-focused therapeutics | journal = ACS Med Chem Lett | volume = 5 | issue = 6 | pages = 623–627 | date = June 2014 | pmid = 24944732 | pmc = 4060932 | doi = 10.1021/ml500113s | url = }}{{cite web | title=Norfenfluramine to treat dravet syndrome | website=Google Patents | date=9 March 2023 | url=https://patents.google.com/patent/US20230076320A1/en | access-date=7 December 2024}}

3-CA is closely related to the potent serotonergic neurotoxin PCA.{{cite journal | vauthors = Fuller RW | title = Effects of p-chloroamphetamine on brain serotonin neurons | journal = Neurochem Res | volume = 17 | issue = 5 | pages = 449–456 | date = May 1992 | pmid = 1528354 | doi = 10.1007/BF00969891 | url = }}{{cite journal | vauthors = Fuller RW | title = Structure-activity relationships among the halogenated amphetamines | journal = Ann N Y Acad Sci | volume = 305 | issue = 1| pages = 147–159 | date = June 1978 | pmid = 152079 | doi = 10.1111/j.1749-6632.1978.tb31518.x | bibcode = 1978NYASA.305..147F | url = }} In contrast to PCA, 3-CA produced no serotonergic neurotoxicity in rodents. However, this was found to be due to rapid metabolism via para-hydroxylation. When the metabolism of 3-CA was inhibited, the drug produced approximately equivalent serotonergic neurotoxicity to PCA.