4-Methylthiomethamphetamine

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).^[1]^[2]^[3] Much less is known about 4-MTMA compared to 4-MTA.^[4]

Other names4-MTMA; N-Methyl-4-methylthioamphetamine; N-Methyl-MTA; NMMTA; PAL-1063; PAL1063

Drug classSerotonin releasing agent; Monoamine oxidase inhibitor; Entactogen

ATC code

None

CAS Number

547736-90-3

Quick facts Clinical data, Other names ...

4-Methylthiomethamphetamine
Clinical data

Other names	4-MTMA; N-Methyl-4-methylthioamphetamine; N-Methyl-MTA; NMMTA; PAL-1063; PAL1063
Drug class	Serotonin releasing agent; Monoamine oxidase inhibitor; Entactogen
ATC code	None
Identifiers
IUPAC name N-methyl-1-(4-methylsulfanylphenyl)propan-2-amine
CAS Number	547736-90-3
PubChem CID	46882957
ChemSpider	24678465
ChEMBL	ChEMBL1078038
Chemical and physical data
Formula	C₁₁H₁₇NS
Molar mass	195.32 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES CC(CC1=CC=C(C=C1)SC)NC
InChI InChI=1S/C11H17NS/c1-9(12-2)8-10-4-6-11(13-3)7-5-10/h4-7,9,12H,8H2,1-3H3 Key:WWHIYWVWPXXBTC-UHFFFAOYSA-N

4-MTMA is known to act as a potent serotonin releasing agent (SRA).^[1]^[3] Its EC₅₀Tooltip half-maximal effective concentration value for induction of serotonin release in rat brain synaptosomes was 21 nM, whereas norepinephrine and dopamine release were not reported.^[3] 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).^[4]^[5]^[6] It is about one-third as potent as 4-MTA as an MAO-A inhibitor.^[5]^[6] Its IC₅₀Tooltip half-maximal inhibitory concentration value for MAO-A inhibition is 0.89 nM, whereas the values of 4-MTA are 0.13 nM for (+)-4-MTA and 2.04 nM for (–)-4-MTA.^[5]^[6] Neither 4-MTA nor 4-MTMA inhibited monoamine oxidase B (MAO-B).^[5]^[6] Potent monoamine oxidase inhibition by amphetamines has been associated with dangerous and sometimes fatal toxicity in humans.^[5]^[6]

In animal drug discrimination tests, 4-MTA and 4-MTMA were found to generalize to MDMA.^[4]^[2]^[7] 4-MTA substituted for the serotonergic agent PMMA, whereas 4-MTMA did not.^[4]^[2]^[7] 4-MTA did not substitute for the serotonergic psychedelic DOM, whereas 4-MTMA was not assessed in DOM-trained animals.^[4]^[2] Neither 4-MTA nor 4-MTMA substituted for the psychostimulants dextroamphetamine or cocaine.^[4]^[2] It was concluded that 4-MTA and 4-MTMA show mainly MDMA-like effects in rodents.^[4]^[2]^[7]

4-MTMA had not been identified as an illicit drug or drug of misuse by 2004.^[2]^[1] However, it is said to have been encountered as a novel designer drug by 2015.^[8]

References

[1]
Murphy J, Flynn JJ, Cannon DM, Guiry PJ, McCormack P, Baird AW, et al. (May 2002). "In vitro neuronal and vascular responses to 5-hydroxytryptamine: modulation by 4-methylthioamphetamine, 4-methylthiomethamphetamine and 3,4-methylenedioxymethamphetamine". Eur J Pharmacol. 444 (1–2): 61–67. doi:10.1016/s0014-2999(02)01586-8. PMID 12191583.
[2]
Khorana N, Pullagurla MR, Dukat M, Young R, Glennon RA (August 2004). "Stimulus effects of three sulfur-containing psychoactive agents". Pharmacol Biochem Behav. 78 (4): 821–826. doi:10.1016/j.pbb.2004.05.021. PMID 15301941. 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.
[3]
Rothman RB, Partilla JS, Baumann MH, Lightfoot-Siordia C, Blough BE (April 2012). "Studies of the biogenic amine transporters. 14. Identification of low-efficacy "partial" substrates for the biogenic amine transporters". The Journal of Pharmacology and Experimental Therapeutics. 341 (1): 251–262. doi:10.1124/jpet.111.188946. PMC 3364510. PMID 22271821.
[4]
Błachut D, Wojtasiewicz K, Czarnocki Z, Szukalski B (November 2009). "The analytical profile of some 4-methylthioamphetamine (4-MTA) homologues". Forensic Sci Int. 192 (1–3): 98–114. doi:10.1016/j.forsciint.2009.08.009. PMID 19766415. 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.
[5]
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. 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).
[6]
Hurtado-Guzmán C, Fierro A, Iturriaga-Vásquez P, Sepúlveda-Boza S, Cassels BK, Reyes-Parada M (August 2003). "Monoamine oxidase inhibitory properties of optical isomers and N-substituted derivatives of 4-methylthioamphetamine" (PDF). J Enzyme Inhib Med Chem. 18 (4): 339–47. doi:10.1080/1475636031000118437. PMID 14567549.
[7]
Dukat M, Young R, Glennon RA (May 2002). "Effect of PMA optical isomers and 4-MTA in PMMA-trained rats". Pharmacol Biochem Behav. 72 (1–2): 299–305. doi:10.1016/s0091-3057(01)00776-6. PMID 11900800.
[8]
Houck MM (2015). Forensic Chemistry. Advanced Forensic Science Series. Academic Press. p. 187. ISBN 978-0-12-800624-5. Retrieved 12 January 2025.

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4-Methylthiomethamphetamine

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