Synthesis and evaluation of substituted 2-phenylcyclobutylamines as analogs of hallucinogenic phenethylamines: lack of LSD-like biological activity
Journal of Medicinal Chemistry – September 01, 1984
Source: OpenAlex
Summary
Trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine demonstrated complete generalization of the LSD cue in a study involving rats, indicating strong hallucinogenic potential. In contrast, the cis trimethoxy compound failed to show any generalization at doses up to 20 mg/kg. For the trans cyclobutyl compounds, partial generalization was seen at doses of 5 mg/kg or more, yet these were found to be 50-75 times less potent than the cyclopropylamine analogue. The findings suggest distinct pharmacological profiles among these phenethylamines and their influence on neurotransmitter receptors.
Abstract
cis- and trans-2-(2,4,5-trimethoxyphenyl)cyclobutylamine and trans-2-(2,5-dimethoxy-4-methylphenyl)cyclobutylamine were synthesized as conformationally restricted analogues of hallucinogenic phenylisopropylamines. In rats trained to discriminate saline from LSD (0.08 mg/kg, ip) in a two-lever drug discrimination paradigm, no generalization of the LSD stimulus to the cis trimethoxy compound occurred at doses up to 20 mg/kg. For both of the trans compounds, partial generalization of the LSD cue occurred at doses of 5 mg/kg or greater. In contrast, complete generalization occurred with trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine. The ED50 for this compound and the doses of the trans cyclobutyl homologues at which significant drug-appropriate responding occurred indicate that the latter are on the order of 50-75 times less potent than the cyclopropylamine analogue. The lack of generalization to the cyclobutylamines indicates either that their discriminative stimulus properties differ from LSD or that they lack discriminative effects.