2,4,5-Trimethoxyamphetamine

Last updated
TMA-2
Trimethoxyamphetamine-2.svg
Clinical data
Other namesTMA-2; 2,4,5-TMA; 2,4,5-Trimethoxy-α-methylphenethylamine; 2,5-Dimethoxy-4-methoxyamphetamine; 4-Methoxy-2,5-dimethoxyamphetamine; DOMeO; DOOMe; DOO
Routes of
administration 		Oral [1] [2]
Drug class Serotonergic psychedelic; Hallucinogen
Legal status
Legal status
Pharmacokinetic data
Duration of action 8–12 hours [1] [2]
Identifiers
  • 1-(2,4,5-trimethoxyphenyl)propan-2-amine
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C12H19NO3
Molar mass 225.288 g·mol−1
3D model (JSmol)
  • CC(CC1=CC(=C(C=C1OC)OC)OC)N
  • InChI=1S/C12H19NO3/c1-8(13)5-9-6-11(15-3)12(16-4)7-10(9)14-2/h6-8H,5,13H2,1-4H3
  • Key:TVSIMAWGATVNGK-UHFFFAOYSA-N

2,4,5-Trimethoxyamphetamine (2,4,5-TMA), also known as TMA-2 or as 2,5-dimethoxy-4-methoxyamphetamine (DOMeO), is a psychedelic drug of the phenethylamine and amphetamine families. [1] [2] It is one of the trimethoxyamphetamine (TMA) series of positional isomers. [1] [2] The drug is also notable in being the 4-methoxylated member of the DOx (i.e., 4-substituted-2,5-dimethoxyamphetamine) series of drugs. [1] [2]

Contents

Use and effects

TMA-2 is a serotonergic psychedelic and produces hallucinogenic effects. [1] [2] It is said to be active at doses of 20 to 40 mg and to have a duration of 8 to 12 hours. [1] [4] It is much more potent than its positional isomer 3,4,5-trimethoxyamphetamine (3,4,5-TMA, TMA, or TMA-1), which is said to be active at doses of 100 to 250 mg and to have a duration of 6 to 8 hours. [5] However, DOM (2,5-dimethoxy-4-methylamphetamine), the analogue of TMA-2 in which its 4-methoxy group has been replaced with a more lipophilic 4-methyl group, is about 10 times more potent than TMA-2. [6]

Interactions

Pharmacology

Pharmacodynamics

TMA-2 activities
Target Affinity (Ki, nM)
5-HT1A >10,000
5-HT1B >10,000
5-HT1D >10,000
5-HT1E >10,000
5-HT1F ND
5-HT2A 57.9–1,300 (Ki)
190–1,860 (EC50 Tooltip half-maximal effective concentration)
84–102% (Emax Tooltip maximal efficacy)
5-HT2B 154–307 (Ki)
270 (EC50)
78% (Emax)
5-HT2C 87.7–5,300
5-HT3 >10,000
5-HT4 ND
5-HT5A >10,000
5-HT6 >10,000
5-HT7 >10,000
α1A, α1B >10,000
α1D ND
α2A–α2C >10,000
β1, β2 >10,000
D1–D5 >10,000
H1 1,407
H2–H4 >10,000
M1, M3, M4 ND
M2, M5 >10,000
TAAR1 >4,400 (Ki) (mouse)
3,100 (Ki) (rat)
ND (EC50) (human)
I1 ND
σ1, σ2 ND
SERT Tooltip Serotonin transporter>10,000 (Ki)
>100,000 (IC50 Tooltip half-maximal inhibitory concentration)
>100,000 (EC50) (rat)
NET Tooltip Norepinephrine transporter>10,000 (Ki)
>100,000 (IC50)
>100,000 (EC50) (rat)
DAT Tooltip Dopamine transporter>10,000 (Ki)
>100,000 (IC50)
>100,000 (EC50) (rat)
MAO-A Tooltip Monoamine oxidase A>100,000 (IC50) (rat)
MAO-B Tooltip Monoamine oxidase B>100,000 (IC50) (rat)
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs: [7] [8] [9] [10] [11] [12] [13] [14] [15]

TMA-2's affinity (Ki) for the serotonin 5-HT2A receptor has been found to be 1,300 nM. [10] Its EC50 Tooltip half-maximal effective concentration at the receptor was 190 nM and its Emax Tooltip maximal efficacy was 84%. [10] The drug was also active at the serotonin 5-HT2B receptor and, to a much lesser extent, at the serotonin 5-HT2C receptor. [10] In an earlier study, its affinities (Ki) were 1,650 nM at the serotonin 5-HT2 receptor and 46,400 nM at the serotonin 5-HT1 receptor. [16] [17] TMA-2 is inactive at the monoamine transporters. [14] [10] It was inactive at the mouse trace amine-associated receptor 1 (TAAR1), whereas it bound to the rat TAAR1 with an affinity (Ki) of 3,100 nM and was not assessed at the human TAAR1. [10]

Chemistry

Derivatives

A variety of derivatives of TMA-2 have been developed and studied. [10] [18]

History

TMA-2 was first described in the scientific literature by Bruckner in 1933. [19] [2] [20] Subsequently, Alexander Shulgin first described the hallucinogenic effects of TMA-2 in 1964. [19] [21] [22] [2]

Society and culture

As of 2011, TMA-2 is not an explicitly controlled substance in the United States. [2] [3] However, it is a positional isomer of 3,4,5-trimethoxyamphetamine (TMA), and thus is a Schedule I controlled substance in states in which isomers are controlled substances. [2] [3]

See also

References

  1. 1 2 3 4 5 6 7 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.
  2. 1 2 3 4 5 6 7 8 9 10 11 Shulgin A, Manning T, Daley PF (2011). "#118. TMA-2". The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds . Vol. 1. Berkeley: Transform Press. ISBN   978-0-9630096-3-0.
  3. 1 2 3 https://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf [ bare URL PDF ]
  4. ↑ 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" (PDF). Neuropharmacology. 167: 107933. doi:10.1016/j.neuropharm.2019.107933. PMC   9191653 . PMID   31917152. Table 4 Human potency data for selected hallucinogens. [...]
  5. ↑ 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.
  6. ↑ Nichols, David E. (2012). "Structure–activity relationships of serotonin 5-HT2A agonists". Wiley Interdisciplinary Reviews: Membrane Transport and Signaling. 1 (5): 559–579. doi: 10.1002/wmts.42 . ISSN   2190-460X.
  7. ↑ "Kᵢ Database". PDSP. 15 March 2025. Retrieved 15 March 2025.
  8. ↑ Liu, Tiqing. "BDBM50005253 (+/-)1-Methyl-2-(2,4,5-trimethoxy-phenyl)-ethylamine::1-(2,4,5-trimethoxyphenyl)propan-2-amine::1-Methyl-2-(2,4,5-trimethoxy-phenyl)-ethylamine::1-Methyl-2-(2,4,5-trimethoxy-phenyl)-ethylamine(2,4,5-TMA)::CHEMBL8389". BindingDB. Retrieved 14 March 2025.
  9. ↑ Ray TS (February 2010). "Psychedelics and the human receptorome". PLOS ONE. 5 (2): e9019. Bibcode:2010PLoSO...5.9019R. doi: 10.1371/journal.pone.0009019 . PMC   2814854 . PMID   20126400.
  10. 1 2 3 4 5 6 7 Kolaczynska KE, Luethi D, Trachsel D, Hoener MC, Liechti ME (2019). "Receptor Interaction Profiles of 4-Alkoxy-Substituted 2,5-Dimethoxyphenethylamines and Related Amphetamines". Front Pharmacol. 10: 1423. doi: 10.3389/fphar.2019.01423 . PMC   6893898 . PMID   31849671.
  11. ↑ Nelson DL, Lucaites VL, Wainscott DB, Glennon RA (January 1999). "Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, -HT(2B) and 5-HT2C receptors" . Naunyn Schmiedebergs Arch Pharmacol. 359 (1): 1–6. doi:10.1007/pl00005315. PMID   9933142.
  12. ↑ Flanagan TW, Billac GB, Landry AN, Sebastian MN, Cormier SA, Nichols CD (April 2021). "Structure-Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore". ACS Pharmacol Transl Sci. 4 (2): 488–502. doi:10.1021/acsptsci.0c00063. PMC   8033619 . PMID   33860179.
  13. ↑ 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" (PDF). Psychopharmacology (Berl). 240 (1): 115–126. doi:10.1007/s00213-022-06279-2. PMC   9816194 . PMID   36477925.
  14. 1 2 Nagai F, Nonaka R, Satoh Hisashi Kamimura K (March 2007). "The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain" . Eur J Pharmacol. 559 (2–3): 132–137. doi:10.1016/j.ejphar.2006.11.075. PMID   17223101.
  15. ↑ 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.
  16. ↑ Glennon RA (January 1987). "Central serotonin receptors as targets for drug research". J Med Chem. 30 (1): 1–12. doi:10.1021/jm00384a001. PMID   3543362. Table II. Affinities of Selected Phenalkylamines for 5-HT1 and 5-HT2 Binding Sites
  17. ↑ Shannon M, Battaglia G, Glennon RA, Titeler M (June 1984). "5-HT1 and 5-HT2 binding properties of derivatives of the hallucinogen 1-(2,5-dimethoxyphenyl)-2-aminopropane (2,5-DMA)". Eur J Pharmacol. 102 (1): 23–29. doi:10.1016/0014-2999(84)90333-9. PMID   6479216.
  18. ↑ Trachsel D (2012). "Fluorine in psychedelic phenethylamines" . Drug Test Anal. 4 (7–8): 577–590. doi:10.1002/dta.413. PMID   22374819.
  19. 1 2 Shulgin AT (1978). "Psychotomimetic Drugs: Structure-Activity Relationships". In Iversen LL, Iversen SD, Snyder SH (eds.). Stimulants. Boston, MA: Springer US. pp. 243–333. doi:10.1007/978-1-4757-0510-2_6. ISBN   978-1-4757-0512-6. 3.1.6. 2,4,5-Trimethoxyphenylisopropylamine This geometric isomer of TMA was first synthesized by Bruckner (1933) and its psychotomimetic properties were first observed some 30 years later (Shulgin, 1964a), 2,4,5-Trimethoxyphenylisopropylamine (34, TMA-2, 2,4,5-trimethoxyamphetamine) was the second of the six possible positional isomers found to be psychotomimetic, and was thus called TMA-2.
  20. ↑ Bruckner, Viktor (24 October 1933). "Über das Pseudonitrosit des Asarons". Journal für Praktische Chemie. 138 (9–10): 268–274. doi:10.1002/prac.19331380907. ISSN   0021-8383.
  21. ↑ Shulgin AT (July 1964). "Psychotomimetic amphetamines: methoxy 3,4-dialkoxyamphetamines". Experientia. 20 (7): 366–367. doi:10.1007/BF02147960. PMID   5855670.
  22. ↑ Shulgin AT (May 1966). "The six trimethoxyphenylisopropylamines (trimethoxyamphetamines)". J Med Chem. 9 (3): 445–446. doi:10.1021/jm00321a058. PMID   5960939.
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