SYNTHESIS AND PRELIMINARY PHARMACOLOGIC EVALUATION OF 2- AND 3-SUBSTITUTED QUINUCLIDINES AS SEMIRIGID ANALOGS OF AMINO ACID NEUROTRANSMITTERS.

摘要

Esters of 2- and 3-substituted quinuclidines were synthesized and evaluated in a preliminary pharmacologic screen. Compounds substituted at the 3 position were prepared from 3-quinuclidinone via the Wittig reaction, catalytic reduction and base-catalyzed alkylation. Preparation of 2-substituted quinuclidinones involved Michael addition of malonate esters to 2-methylene-3-quinuclidinone. Following acid hydrolysis, decarboxylation and re-esterification, the keto-esters were reduced to the corresponding alcohols using sodium borohydride. The Wittig reaction utilizing 2-quinuclidinecarboxaldehyde afforded additional 2-substituted quinuclidines.;Pharmacologic evaluation revealed the ability of several compounds to induce excitation and seizures in mice. At low doses they enhanced the seizure inducing potency of metrazole. Varying degrees of protection from seizures were afforded by mecamylamine and diazepam. The structural similarity evident between these agents, GABA and acetylcholine suggests a "mixed" pharmacologic profile.