4-Methylthiomethamphetamine

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| image = 4-Methylthiomethamphetamine.svg

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| class = Serotonin releasing agent; Monoamine oxidase inhibitor; Entactogen

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| CAS_number = 547736-90-3

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| PubChem = 46882957

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| ChemSpiderID = 24678465

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| ChEMBL = 1078038

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| synonyms = 4-MTMA; N-Methyl-4-methylthioamphetamine; N-Methyl-MTA; NMMTA; PAL-1063; PAL1063

| IUPAC_name = N-methyl-1-(4-methylsulfanylphenyl)propan-2-amine

| C=11 | H=17 | N=1 | S=1

| SMILES = CC(CC1=CC=C(C=C1)SC)NC

| StdInChI = 1S/C11H17NS/c1-9(12-2)8-10-4-6-11(13-3)7-5-10/h4-7,9,12H,8H2,1-3H3

| StdInChIKey = WWHIYWVWPXXBTC-UHFFFAOYSA-N

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4-Methylthiomethamphetamine (4-MTMA; code name PAL-1063), also known as N-methyl-4-methylthioamphetamine (NMMTA), is a monoamine releasing agent (MRA) of the amphetamine family related to 4-methylthioamphetamine (4-MTA) and N,N-dimethyl-4-methylthioamphetamine (DMMTA or 4-MTDMA).{{cite journal | vauthors = Murphy J, Flynn JJ, Cannon DM, Guiry PJ, McCormack P, Baird AW, McBean GJ, Keenan AK | title = In vitro neuronal and vascular responses to 5-hydroxytryptamine: modulation by 4-methylthioamphetamine, 4-methylthiomethamphetamine and 3,4-methylenedioxymethamphetamine | journal = Eur J Pharmacol | volume = 444 | issue = 1–2 | pages = 61–67 | date = May 2002 | pmid = 12191583 | doi = 10.1016/s0014-2999(02)01586-8 | url = }}{{cite journal | vauthors = Khorana N, Pullagurla MR, Dukat M, Young R, Glennon RA | title = Stimulus effects of three sulfur-containing psychoactive agents | journal = Pharmacol Biochem Behav | volume = 78 | issue = 4 | pages = 821–826 | date = August 2004 | pmid = 15301941 | doi = 10.1016/j.pbb.2004.05.021 | url = | quote = The present investigation examined these agents, and the N-monomethyl analog of 4-MTA (i.e., 4-MTMA), in tests of stimulus generalization (substitution) using a two-lever drug discrimination task with groups of rats trained to discriminate either the hallucinogen DOM [1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane], the stimulant cocaine, or the empathogen MDMA from vehicle. 4-MTA and its N-monomethyl analog 4-MTMA (ED50 = 0.8 mg/kg in both cases) substituted only for the MDMA stimulus, whereas 2C-T-7 (ED50 = 0.8 mg/kg) substituted only for the DOM stimulus. Thus, at the doses examined, 4-MTA and 4-MTMA appear to be MDMA-like agents, and 2C-T-7 seems best classified as a DOM-like hallucinogen. }} Much less is known about 4-MTMA compared to 4-MTA.{{cite journal | vauthors = Błachut D, Wojtasiewicz K, Czarnocki Z, Szukalski B | title = The analytical profile of some 4-methylthioamphetamine (4-MTA) homologues | journal = Forensic Sci Int | volume = 192 | issue = 1–3 | pages = 98–114 | date = November 2009 | pmid = 19766415 | doi = 10.1016/j.forsciint.2009.08.009 | url = | quote = Whereas pharmacological properties of 4-MTA are well described in the literature, much less is known about its N-methylated homologue, 4-methylthiomethamphetamine (4- MTMA). The 4-MTMA has been examined in the test of stimulus generalization using MDMA and PMMA-trained rats [11,12]. Because the stimulus generalization failed to occur with PMMA and instead the substitution took place upon the administration of 4-MTMA to MDMA-trained animals, the drug was considered to be a MDMA-like agent. Only one study was devoted to the biological activity of N-alkyl derivatives of 4-MTA with substituents other than N-methyl [16]. An important conclusion of this work was that all derivatives investigated, including 4-MTA and its N-methyl, Nethyl, N-propyl and N,N-dimethyl-homologues, acted as selective, reversible inhibitors of MAO-A and their potency decreased with the increasing size of the N-alkyl chain. }}

4-MTMA is known to act as a potent serotonin releasing agent (SRA). Its {{Abbrlink|EC₅₀|half-maximal effective concentration}} value for induction of serotonin release in rat brain synaptosomes was 21{{nbsp}}nM, whereas norepinephrine and dopamine release were not reported.{{cite journal | vauthors = Rothman RB, Partilla JS, Baumann MH, Lightfoot-Siordia C, Blough BE | title = Studies of the biogenic amine transporters. 14. Identification of low-efficacy "partial" substrates for the biogenic amine transporters | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 341 | issue = 1 | pages = 251–262 | date = April 2012 | pmid = 22271821 | pmc = 3364510 | doi = 10.1124/jpet.111.188946 }} In addition to its MRA activity, like 4-MTA, the drug has been found to act as a potent reversible enzyme inhibitor of monoamine oxidase A (MAO-A).{{cite journal | vauthors = Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK | title = Amphetamine Derivatives as Monoamine Oxidase Inhibitors | journal = Front Pharmacol | volume = 10 | issue = | pages = 1590 | date = 2019 | pmid = 32038257 | pmc = 6989591 | doi = 10.3389/fphar.2019.01590 | doi-access = free | url = | quote = Relatively few amino group substituents have been studied in AMPH derivatives regarding their influence upon MAOI potency. In general terms, any N-substitution leads to a decrease in the activity of the compound as a MAOI-A. Thus, the N-methyl derivatives of AMPH, MTA, p-methoxyAMPH (PMA), and 3,4-methylenedioxyAMPH (MDA)— i.e. methamphetamine, NMMTA, PMMA, and MDMA respectively— have about one-third the inhibitory potency of their corresponding primary amine congeners (Scorza et al., 1997; Hurtado-Guzmán et al., 2003; Matsumoto et al., 2014; Santillo, 2014; Tables 1, 2, 4). }}{{cite journal | vauthors = Hurtado-Guzmán C, Fierro A, Iturriaga-Vásquez P, Sepúlveda-Boza S, Cassels BK, Reyes-Parada M | title = Monoamine oxidase inhibitory properties of optical isomers and N-substituted derivatives of 4-methylthioamphetamine | journal = J Enzyme Inhib Med Chem | volume = 18 | issue = 4 | pages = 339–47 | date = August 2003 | pmid = 14567549 | doi = 10.1080/1475636031000118437 | url = https://repositorio.uchile.cl/bitstream/handle/2250/119450/Hurtado_Guzman_Claudio.pdf }} It is about one-third as potent as 4-MTA as an MAO-A inhibitor. Its {{Abbrlink|IC₅₀|half-maximal inhibitory concentration}} value for MAO-A inhibition is 0.89{{nbsp}}nM, whereas the values of 4-MTA are 0.13{{nbsp}}nM for (+)-4-MTA and 2.04{{nbsp}}nM for (–)-4-MTA. Neither 4-MTA nor 4-MTMA inhibited monoamine oxidase B (MAO-B). Potent monoamine oxidase inhibition by amphetamines has been associated with dangerous and sometimes fatal toxicity in humans.

In animal drug discrimination tests, 4-MTA and 4-MTMA were found to generalize to MDMA.{{cite journal | vauthors = Dukat M, Young R, Glennon RA | title = Effect of PMA optical isomers and 4-MTA in PMMA-trained rats | journal = Pharmacol Biochem Behav | volume = 72 | issue = 1–2 | pages = 299–305 | date = May 2002 | pmid = 11900800 | doi = 10.1016/s0091-3057(01)00776-6 | url = }} 4-MTA substituted for the serotonergic agent PMMA, whereas 4-MTMA did not. 4-MTA did not substitute for the serotonergic psychedelic DOM, whereas 4-MTMA was not assessed in DOM-trained animals. Neither 4-MTA nor 4-MTMA substituted for the psychostimulants dextroamphetamine or cocaine. It was concluded that 4-MTA and 4-MTMA show mainly MDMA-like effects in rodents.

4-MTMA had not been identified as an illicit drug or drug of misuse by 2004. However, it is said to have been encountered as a novel designer drug by 2015.{{cite book | vauthors = Houck MM | title=Forensic Chemistry | publisher=Academic Press | series=Advanced Forensic Science Series | year=2015 | isbn=978-0-12-800624-5 | url=https://books.google.com/books?id=POpDBAAAQBAJ&pg=PA187 | access-date=12 January 2025 | page=187}}