1-(2,5-Dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane: a potent serotonin 5-HT2A/2C agonist

J Med Chem. 1994 Dec 9;37(25):4346-51. doi: 10.1021/jm00051a011.


A method was found to synthesize 1-(2,5-dimethoxy-4-(trifluoromethyl) phenyl)-2-aminopropane, 5, and its des-alpha-methyl congener 2-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)aminoethane, 6, the trifluoromethyl analogs of substituted hallucinogenic phenethylamine derivatives such as 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (3, DOI) that are potent 5-HT2A/2C agonists. In our hands, 5 and 6 have proven to have affinity for [3H]ketanserin or [125I]-3-labeled 5-HT2A/2C sites in rat cortex comparable to or higher than the analogous bromo or iodo analogs. Similarly, 5 and 6 had potency comparable to or slightly greater than that of their bromo or iodo congeners in the two-lever drug discrimination assay in rats trained to discriminate saline from LSD tartrate. The agonist properties of 5 and 6 were evaluated by measuring the accumulation of [3H]inositol monophosphate in cultured cells selectively expressing either 5-HT2A or 5-HT2C receptors. In comparison to serotonin (5-HT), compounds 3 (DOI), 5, and 6 were equally efficacious and full agonists at the 5-HT2C receptor. Similarly, 3 and 5 produced equivalent responses at the 5-HT2A receptor as compared to 5-HT. In contrast, 6, the alpha-desmethyl analog of 5, was only half as potent at stimulating inositol monophosphate accumulation at the 5-HT2A receptor. In conclusion, the title compound 5 and its alpha-desmethyl congener 6 appear to be the most potent of the so-called hallucinogenic amphetamine 5-HT agonists reported to date. Further, the reduced efficacy of 6 at the 5-HT2A receptor may offer at least a partial explanation for the observed higher in vivo potencies of alpha-methyl-substituted compounds in this series.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells / metabolism
  • 8-Hydroxy-2-(di-n-propylamino)tetralin / metabolism
  • Animals
  • Binding, Competitive
  • Cell Line
  • Discrimination, Psychological
  • Frontal Lobe / metabolism
  • Hippocampus / metabolism
  • Iodine Radioisotopes
  • Ketanserin / metabolism
  • Male
  • Mice
  • Phenethylamines / chemical synthesis*
  • Phenethylamines / metabolism
  • Phenethylamines / pharmacology
  • Phosphatidylinositols / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Serotonin / metabolism
  • Serotonin / metabolism
  • Serotonin / pharmacology
  • Serotonin Receptor Agonists / chemical synthesis*
  • Serotonin Receptor Agonists / metabolism
  • Serotonin Receptor Agonists / pharmacology
  • Tritium


  • 1-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-2-aminopropane
  • Iodine Radioisotopes
  • Phenethylamines
  • Phosphatidylinositols
  • Receptors, Serotonin
  • Serotonin Receptor Agonists
  • Tritium
  • Serotonin
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • Ketanserin