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3,4,5-Trimethoxyamphetamine

Clinical data
Other names	Trimethoxyamphetamine; TMA; TMA-1; 3,4,5-TMA; α-Methylmescaline; alpha-Methylmescaline; AMM; Mescalamphetamine; 3,4,5-Trimethoxy-α-methylphenethylamine
Drug class	Serotonergic psychedelic; Hallucinogen; Serotonin 5-HT2A receptor agonist
Identifiers
IUPAC name 1-(3,4,5-trimethoxyphenyl)propan-2-amine
CAS Number	1082-88-8
PubChem CID	31016
DrugBank	DB01516
ChemSpider	28775
UNII	P2K02L3YON
KEGG	C22747
ChEMBL	ChEMBL30336
Chemical and physical data
Formula	C12H19NO3
Molar mass	225.288 g·mol
3D model (JSmol)	Interactive image
SMILES CC(CC1=CC(=C(C(=C1)OC)OC)OC)N
InChI InChI=1S/C12H19NO3/c1-8(13)5-9-6-10(14-2)12(16-4)11(7-9)15-3/h6-8H,5,13H2,1-4H3 Key:WGTASENVNYJZBK-UHFFFAOYSA-N

Trimethoxyamphetamine (TMA or TMA-1), also known as 3,4,5-trimethoxyamphetamine (3,4,5-TMA), α-methylmescaline, or mescalamphetamine, is a psychedelic drug of the phenethylamine and amphetamine families. It is one of the trimethoxyamphetamine (TMA) series of positional isomers. The drug is notable in being the amphetamine (i.e., α-methylated) analogue of mescaline (3,4,5-trimethoxyphenethylamine).

TMA is said to be active at doses of 100 to 250 mg and to have a duration of 6 to 8 hours. For comparison, mescaline is typically used at doses of 200 to 500 mg and is said to have a duration of 10 to 12 hours or longer. TMA's positional isomer 2,4,5-trimethoxyamphetamine (2,4,5-TMA or TMA-2) is much more potent than TMA, with a dosage of 20 to 40 mg and a duration of 8 to 12 hours.

TMA is a low-potency serotonin 5-HT_2A receptor partial agonist, with an affinity (K_i) of >12,000 nM, an EC₅₀Tooltip half-maximal effective concentration of 1,700 nM, and an E_maxTooltip maximal efficacy of 40%. Conversely, it was inactive at the serotonin 5-HT_1A, 5-HT_2B and 5-HT_2C receptors and at several other receptors, at least at the assessed concentrations (up to 10,000 nM). It showed affinity for the mouse and rat trace amine-associated receptor 1 (TAAR1) (K_i = 1,800 nM and 3,200 nM, respectively), whereas it was inactive at the human TAAR1 (EC₅₀ > 10,000 nM).

TMA is also a very low-potency serotonin releasing agent (SRA), with an EC₅₀ value of 16,000 nM. In contrast, it is inactive as a releasing agent and reuptake inhibitor of dopamine and norepinephrine (EC₅₀ > 100,000 nM). Despite its apparent SRA activity in vitro, TMA did not increase brain serotonin or dopamine levels in rodents in vivo. TMA is similarly inactive as a monoamine oxidase inhibitor (MAOI), including of both monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) (IC₅₀Tooltip half-maximal inhibitory concentration > 200,000 nM).

The low potency of TMA as a serotonin 5-HT_2A receptor agonist is analogous to the case of mescaline, which is a well-known and widely used psychedelic but is likewise a very low-potency agonist of this receptor, showing an affinity (K_i) of 9,400 nM, an EC₅₀ of 10,000 nM, and an E_max of 56% in the same study. For comparison, DOM has shown an affinity (K_i) of 88 nM and an EC₅₀ of 4 to 24 nM.

See also

• α-Ethylmescaline
• 3,4-Dimethoxyamphetamine

References

1. ^ Shulgin AT, Shulgin A (1991). "#157 TMA 3,4,5-TRIMETHOXYAMPHETAMINE". PiHKAL: A Chemical Love Story (1st ed.). Berkeley, CA: Transform Press. ISBN 9780963009609. OCLC 25627628.
2. ^ Shulgin A, Manning T, Daley PF (2011). "#117. TMA". The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. Vol. 1. Berkeley: Transform Press. ISBN 978-0-9630096-3-0.
3. Halberstadt AL, Luethi D, Hoener MC, Trachsel D, Brandt SD, Liechti ME (January 2023). "Use of the head-twitch response to investigate the structure-activity relationships of 4-thio-substituted 2,5-dimethoxyphenylalkylamines". Psychopharmacology. 240 (1). Berlin: 115–126. doi:10.1007/s00213-022-06279-2. PMC 9816194. PMID 36477925. For example, 3,4,5-trimethoxyamphetamine (TMA) is active at a dose range of 100–250 mg, whereas its 2,4,5-regioisomer (2,4,5-trimethoxyamphetamine, TMA-2) is active at 20–40 mg (Shulgin and Shulgin 1991).
4. Vamvakopoulou IA, Narine KA, Campbell I, Dyck JR, Nutt DJ (January 2023). "Mescaline: The forgotten psychedelic". Neuropharmacology. 222: 109294. doi:10.1016/j.neuropharm.2022.109294. PMID 36252614.
5. Shulgin AT, Shulgin A (1991). "#158 TMA-2 2,4,5-TRIMETHOXYAMPHETAMINE". PiHKAL: A Chemical Love Story (1st ed.). Berkeley, CA: Transform Press. ISBN 9780963009609. OCLC 25627628.
6. ^ Kolaczynska KE, Luethi D, Trachsel D, Hoener MC, Liechti ME (2021). "Receptor Interaction Profiles of 4-Alkoxy-3,5-Dimethoxy-Phenethylamines (Mescaline Derivatives) and Related Amphetamines". Frontiers in Pharmacology. 12: 794254. doi:10.3389/fphar.2021.794254. PMC 8865417. PMID 35222010.
7. ^ Nagai F, Nonaka R, Satoh Hisashi Kamimura K (March 2007). "The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain". European Journal of Pharmacology. 559 (2–3): 132–137. doi:10.1016/j.ejphar.2006.11.075. PMID 17223101.
8. ^ Matsumoto T, Maeno Y, Kato H, Seko-Nakamura Y, Monma-Ohtaki J, Ishiba A, et al. (August 2014). "5-hydroxytryptamine- and dopamine-releasing effects of ring-substituted amphetamines on rat brain: a comparative study using in vivo microdialysis". European Neuropsychopharmacology. 24 (8): 1362–1370. doi:10.1016/j.euroneuro.2014.04.009. PMID 24862256.
9. Reyes-Parada M, Iturriaga-Vasquez P, Cassels BK (2019). "Amphetamine Derivatives as Monoamine Oxidase Inhibitors". Frontiers in Pharmacology. 10: 1590. doi:10.3389/fphar.2019.01590. PMC 6989591. PMID 32038257.
10. Luethi D, Rudin D, Hoener MC, Liechti ME (2022). "Monoamine Receptor and Transporter Interaction Profiles of 4-Alkyl-Substituted 2,5-Dimethoxyamphetamines". The FASEB Journal. 36 (S1). doi:10.1096/fasebj.2022.36.S1.R2691. ISSN 0892-6638.

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