Synthesis and evaluation of substituted 2-phenylcyclobutylamines as analogues of hallucinogenic phenethylamines: lack of LSD-like biological activity.
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.
D000818:Animals; D003503:Cyclobutanes / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D010627:Phenethylamines; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship
D003503:Cyclobutanes; C031182:LSD receptor; D010627:Phenethylamines; D011985:Receptors, Serotonin; C042530:2-(2,5-dimethoxy-4-methylphenyl)cyclobutylamine; C042529:2-(2,4,5-trimethoxyphenyl)cyclobutylamine