4-Anilidopiperidine analgesics. 2. A study of the conformational aspects of the analgesic activity of the 4-anilidopiperidines utilizing isomeric N-substituted 3-(propananilido)nortropane analogs

Abstract

Relatively little information is available concerning the influence of conformational factors on the potent analgesic actions of the 4-anilidopiperidines. A series of N-substituted 3.alpha.- and 3.beta.-(propananilido)nortropane were designed, synthesized and stereochemically characterized as semirigid analogs of the 4-anilidopiperidine analgesics to study the influence of certain stereochemical factors on analgesia in this class of compounds. Conformational analysis of 3.alpha.-propananilides reveals a boat conformation for the preferred conformation of the piperidine ring of the tropan analogs. Evaluation of the analgesic potencies in mice of the isomeric N-substituted 3-(propananilido)nortropanes indicates greater potency for the 3.beta.-(propananilido) isomers with N-benzyl and N-phenethyl substitution as compared to the corresponding N-substituted 3.alpha.-propananilides. Analysis of relative solubility differences among the isomers suggests that both structural and stereochemical influences predominate in affecting analgesic potency.