IMETHOXY-4-(TRIFLUOROMETHYL)PHENYL)-2-AMINOPROPANE - A POTENT SEROTONIN 5-HT2A 2C AGONIST/

A method was found to synthesize methoxy-4-(trifluoromethyl)phenyl)-2- aminopropane, 5, and its des-alpha-methyl congener 5-dimethoxy-4-(trif luoromethyl)phenyl)aminoethane, 6, the trifluoromethyl analogs of Subs tituted hallucinogenic phenethylamine derivatives such as 1-(2,5-dimet hoxy-4-iodophenyl)-2-aminopropane (3, DOI) that are potent 5-HT2A/2C a gonists. In our hands, 5 and 6 have proven to have affinity for [H-3]k etanserin or [I-125]-3-labeled 5-HT2A2C sites in rat cortex comparable to or higher than the analogous bromo or iodo analogs. Similarly, 5 a nd 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 pro perties of 5 and 6 were evaluated by measuring the accumulation of [H- 3]inositol monophosphate in cultured cells selectively expressing eith er 5-HT2A or 5-HT2C receptors. In comparison to serotonin (5-HT), comp ounds 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 rec eptor may offer at least a partial explanation for the observed higher in vivo potencies of alpha-methyl-substituted compounds in this serie s.