Synthesis and evaluation of 2,3-dihydrobenzofuran analogs of the hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane: drug discrimination studies in rats

Two new chemical analogues of the hallucinogen DOM were created and tested in rats trained to distinguish LSD from saline. Both analogues produced LSD-like effects, but only at doses more than ten times higher than DOM. The authors suggest this weakened activity may be due to the orientation of oxygen atoms in the analogues, which may not fit a specific binding site on the brain receptor.

Study at a glance

Abstract

Two analogues, 6-(2-aminopropyl)-5-methoxy-2,3-dihydrobenzofuran and 6-(2-aminopropyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran, of the hallucinogenic agent 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) were synthesized and tested in the two-lever drug discrimination paradigm. In rats trained to discriminate saline from LSD tartrate (0.08 mg/kg), stimulus generalization occurred to both of the 2,3-dihydrobenzofuran analogues but at doses more than 10-fold higher than for DOM. A possible explanation for this dramatic attenuation of LSD-like activity could involve a highly directional electrophilic binding site on the receptor that cannot accept the orientation of the unshared electron pairs on the heterocyclic oxygen atom in the benzofurans.