2,5-Dimethoxy-4-trifluoromethylamphetamine explained

2,5-Dimethoxy-4-trifluoromethylamphetamine (DOTFM) is a psychedelic drug of the phenethylamine, amphetamine, and DOx. It was first synthesized in 1994 by a team at Purdue University led by David E. Nichols.[1] DOTFM is the α-methylated analogue of 2C-TFM.

It acts as an agonist at the serotonin 5-HT2A and 5-HT2C receptors.[1] In drug discrimination tests in rats, DOTFM fully substituted for LSD and was slightly more potent than DOI.[1] In addition, (R)-DOTFM robustly induces the head-twitch response, a behavioral proxy of psychedelic effects, in rodents, with equivalent potency as (R)-DOI. The drug is around twice as potent as 2C-TFM in animal studies.

In contrast to (R)-DOI, which has extraordinarily potent serotonin 5-HT2A receptor-mediated anti-inflammatory effects,[2] [3] DOTFM shows no anti-inflammatory effects.[4] The differences between the drugs in this regard appear to be due to differences in functional selectivity at the serotonin 5-HT2A receptor.[5]

Notes and References

  1. Bryan Roth . Nichols DE, Frescas S, Marona-Lewicka D, Huang X, Roth BL, Gudelsky GA, Nash JF . 1-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane: a potent serotonin 5-HT2A/2C agonist . Journal of Medicinal Chemistry . 1994 . 37 . 25 . 4346–4351 . 7996545 . 10.1021/jm00051a011 .
  2. Nichols DE, Johnson MW, Nichols CD . Psychedelics as Medicines: An Emerging New Paradigm . Clin Pharmacol Ther . 101 . 2 . 209–219 . February 2017 . 28019026 . 10.1002/cpt.557 .
  3. Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD . Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency . J Pharmacol Exp Ther . 327 . 2 . 316–323 . November 2008 . 18708586 . 10.1124/jpet.108.143461 .
  4. Flanagan . Thomas W. . Billac . Gerald . Nichols . Charles D. . Differential Regulation of Inflammatory Responses Following 5‐HT 2 Receptor Activation in Pulmonary Tissues . The FASEB Journal . 36 . S1 . 2022 . 0892-6638 . 10.1096/fasebj.2022.36.S1.R2617 .
  5. Flanagan TW, Foster TP, Galbato TE, Lum PY, Louie B, Song G, Halberstadt AL, Billac GB, Nichols CD . Serotonin-2 Receptor Agonists Produce Anti-inflammatory Effects through Functionally Selective Mechanisms That Involve the Suppression of Disease-Induced Arginase 1 Expression . ACS Pharmacol Transl Sci . 7 . 2 . 478–492 . February 2024 . 38357283 . 10863441 . 10.1021/acsptsci.3c00297 . The effects of (R)-DOTFM were examined in the head-twitch response (HTR) assay. (R)-DOTFM produced a strong HTR with a potent ED 50 of 0.60 μmol/kg. These values are equivalent to (R)-DOI, as previously determined. .

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