3,4,5-Trimethoxytranylcypromine
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| Other names | TMT; MCPA; trans-2-(3,4,5-Trimethoxyphenyl)cyclopropylamine |
| Drug class | Possible serotonergic psychedelic or hallucinogen |
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| Formula | C12H17NO3 |
| Molar mass | 223.272 g·mol−1 |
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3,4,5-Trimethoxytranylcypromine (TMT), also known as MCPA as well as trans-2-(3,4,5-trimethoxyphenyl)cyclopropylamine, is a possible psychedelic drug of the phenethylamine, scaline, and phenylcyclopropylamine families related to mescaline (3,4,5-trimethoxyphenethylamine).[1][2][3][4] It is a cyclized phenethylamine and the analogue of mescaline in which the α and β positions of the ethyl side chain have been cyclized to form a cyclopropane ring.[2][3][4] The drug may also be thought of as a structural hybrid between mescaline and the antidepressant tranylcypromine.[2][5][6]
Use and effects
[edit]In his book PiHKAL (Phenethylamines I Have Known and Loved), Alexander Shulgin reported that TMT produced no central effects at a dose of 13 mg orally.[2] Higher doses were not assessed.[2]
Pharmacology
[edit]TMT has been reported to produce mescaline-like effects in animals with similar or slightly greater potency than mescaline but a slightly shorter duration.[7][5][6][8][3][4] TMT is the trans isomer of a pair of cis and trans isomers, and it is specifically the trans isomer that is active.[7][6][8][9][10][11][3][4]
History
[edit]TMT was first described in the scientific literature by G. C. Walters and P. D. Cooper in 1968.[5] Alexander Shulgin subsequently described evaluating a low dose of TMT in humans in his 1991 book PiHKAL (Phenethylamines I Have Known and Loved).[2] TMT was one of the earliest psychedelic-related cyclized phenethylamines to be evaluated.[7][3][4] Subsequently, the much more potent 2,5-dimethoxy-4-methylphenylcyclopropylamine (DMCPA) was developed.[3][4]
See also
[edit]- Substituted methoxyphenethylamine
- Cyclized phenethylamine
- Phenylcyclopropylamine
- Substituted mescaline analogue
- 2,5-Dimethoxy-4-methylphenylcyclopropylamine (DMCPA)
References
[edit]- ^ Shulgin A, Manning T, Daley P (2011). The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. Vol. 1. Berkeley: Transform Press. pp. 74, 350. ISBN 978-0-9630096-3-0.
- ^ a b c d e f Shulgin A, Shulgin A (September 1991). PiHKAL: A Chemical Love Story. Berkeley, California: Transform Press. ISBN 0-9630096-0-5. OCLC 25627628. "The placement of the methyl group between the two carbons (so to speak) produces a cyclopropyl system. The simplest example is 2-phenylcyclopropylamine, a drug with the generic name of tranylcypromine and the trade name Parnate. It is a monoamine oxidase inhibitor and has been marketed as an antidepressant, but the compound is also a mild stimulant causing insomnia, restlessness and photophobia. Substitutions on the benzene ring of this system have not been too promising. The DOM analogue, 2,5-dimethoxy-4-methyltranylcypromine is active in man, and is discussed in its own recipe under DMCPA. The inactive mescaline analogue TMT is also mentioned there." [...] "This compound, DMCPA, was modeled directly after the structure of DOM, with the 2,5-dimethoxy-4-methyl substitution pattern. Another analogue of tranylcypromine, similarly modeled, is 3,4,5-trimethoxytranylcypromine, or trans-2-(3,4,5-trimethoxyphenyl)cyclopropylamine (TMT). It has been evaluated at levels of only 13 milligrams orally, and at this dose there were no hints of central activity."
- ^ a b c d e f Nichols DE (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.
Incorporation of the α-methyl into a cyclopropane ring gives substituted 2-phenylcyclopropylamines with high potency, both in vitro and in vivo. In vivo potency for the cis- and trans-cyclopropane analogs of mescaline was first reported by Cooper and Walters.94,95 These workers found that the trans compound 59 produced effects in rodents that qualitatively resembled mescaline, with a potency somewhat greater than mescaline and a slightly shorter duration of action (Figure 26). Aldous et al.50 subsequently explored several cyclopropane analogs of substituted amphetamines. Although it was not then possible to measure receptor effects, production of hyperthermia in rabbits as well as producing changes in cat encephaolgram (EEG) were taken as indicators of possible hallucinogenic action, which we now know is correlated with actions at the 5-HT2A receptor. In particular, the trans-2,4,5- trimethoxy 60 and trans-2,5-dimethoxy-4-methyl compounds 61 had hallucinogen-like activity, with about 20 and 35%, respectively, of the activity of DOM.
- ^ a b c d e f Nichols DE (2018). Chemistry and Structure-Activity Relationships of Psychedelics. Current Topics in Behavioral Neurosciences. Vol. 36. pp. 1–43. doi:10.1007/7854_2017_475. ISBN 978-3-662-55878-2. PMID 28401524.
Incorporating the alpha methyl into a cyclopropane ring gives substituted 2-phenylcyclopropylamines with high in vitro and in vivo potency. The cis and trans cyclopropane analogues of mescaline were first reported by Cooper and Walters, who found that trans compound 64 produced an effect in rodents qualitatively resembling mescaline, but with a potency slightly greater than mescaline (Walters and Cooper 1968; Cooper and Walters 1972). Subsequently Aldous et al. (1974) explored cyclopropane analogues of several substituted amphetamines. Using an assay that measured hyperthermia in rabbits, as well as assessing changes in cat EEG, trans-2,4,5-trimethoxy compound 65 and trans-2,5-dimethoxy-4-methyl compound 66 (DMCPA) had hallucinogen-like activity, with about 20 and 35%, respectively, of the activity of DOM (37).
- ^ a b c Walters GC, Cooper PD (1968). "Alicyclic Analogue of Mescaline". Nature. 218 (5138): 298–300. Bibcode:1968Natur.218..298W. doi:10.1038/218298a0. ISSN 0028-0836. PMID 5648238.
- ^ a b c Cooper PD (15 December 1970). "Stereospecific synthesis of cis - and trans -2-(3,4,5-trimethoxyphenyl)-cyclopropylamines". Canadian Journal of Chemistry. 48 (24): 3882–3888. doi:10.1139/v70-653. ISSN 0008-4042. Retrieved 26 July 2025.
- ^ a b c Brimblecombe RW, Pinder RM (1975). "Phenylalkylamines and Their Derivatives". Hallucinogenic Agents. Bristol: Wright-Scientechnica. pp. 55–97.
Table 3.8.—RELATIVE HALLUCINOGENIC POTENCIES OF SOME 2-PHENYLCYCLOPROPYLAMINES [...]
- ^ a b Cooper PD, Walters GC (1972). "Stereochemical Requirements of the Mescaline Receptor". Nature. 238 (5359): 96–98. Bibcode:1972Natur.238...96C. doi:10.1038/238096a0. ISSN 0028-0836. PMID 4557788. Retrieved 26 July 2025.
- ^ Nichols DE, Weintraub HJ, Pfister WR, Yim GK (1978). "The use of rigid analogues to probe hallucinogen receptors" (PDF). NIDA Research Monograph (22): 70–83. PMID 101889. Archived from the original (PDF) on August 5, 2023.
[Cooper and Walters (1972)] demonstrated mescaline-like activity in animals for trans-2-(3,4,5-trimethoxyphenyl)-cyclopropylamine 1. In contrast, the cis isomer would have been expected to be more active on the basis of the indole mimicry hypothesis. More recently, Aldous et al. (1974) examined a series of 2-phenylcyclopropylamines as potential hallucinogens. Notable in this study were the results obtained for trans-2-(2,5-dimethoxy-4-methylphenyl)-cyclopropylamine 2, an analogue of DOM. This compound was reported to have about one-third the potency of DOM. These studies led to the clear conclusion that the side chain of the phenethylamine hallucinogens must assume a transoid conformation.
- ^ Nichols DE (August 1981). "Structure-activity relationships of phenethylamine hallucinogens". Journal of Pharmaceutical Sciences. 70 (8): 839–849. Bibcode:1981JPhmS..70..839N. doi:10.1002/jps.2600700802. PMID 7031221.
Rigid Analogs—Several rigid analogs of phenethylamine hallucinogens have been evaluated to elucidate the binding conformation of the side chain. To date, none has been particularly revealing, although some interesting findings have emerged. The simplest rigid analogs are the substituted 2-phenylcyclopropylamines. The 3,4,5-trimethoxy compounds (XXX and XXXI) first were prepared as mescaline analogs (101). Inactivity for the cis-isomer (XXXI) seems to establish conclusively the side-chain binding conformation as trans in the flexible phenethylamines.
- ^ Nichols DE (1994). "Medicinal Chemistry and Structure-Activity Relationships". In Cho AK, Segal DS (eds.). Amphetamine and Its Analogs: Psychopharmacology, Toxicology, and Abuse. Academic Press. pp. 3–41. ISBN 978-0-12-173375-9.
However, the α-methyl group of the amphetamine can be incorporated into a cyclopropane ring with retention of activity. Cooper and Walters (1972) first compared the cis and trans cyclopropylamine analogs of mescaline for behavioral activity in rat. Only the trans compound (45) was active. Aldous et al. (1974) subsequently examined several trans cyclopropylamine analogs of hallucinogenic amphetamines. This group reported that these congeners had activity and potency similar to those of their amphetamine counterparts. The cyclopropylamine analog of DOM, DMCPA (46), first reported by this group subsequently was resolved into its enantiomers, which were tested by Nichols et al. (1979). The 1R,2S-(-) enantiomer (46, as shown) proved to be most active. This result is, perhaps, not surprising since the stereochemistry at the a carbon of the cyclopropyl ring is identical to that of the R isomer of the amphetamines. Further, although the difference in affinity for the 5-HT2 receptor between the Rand S enantiomers of the amphetamines was small, Johnson et al. (1990b) reported that the enantiomer of DMCPA have a ~30-fold difference in affinity.
External links
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