Synthesis and cardiac electrophysiological activity of 2- and 3-[(substituted phenyl)alkyl]quinuclidines....

The syntheses and cardiac electrophysiological effects of 21 2- and 3-substituted quinuclidines and some quaternary ammonium derivatives are described. The 2-substituted quinuclidines 2-8 were prepared by alkylation of 2-methylene-3-quinuclidinone. The Wittig reaction with 3-quinuclidinone afforded the 3-substituted derivative 9, which was subsequently converted to 10 and 11. The electrophysiological profiles of the compounds were determined in canine cardiac Purkinje fibers and ventricular muscle strips. The 3-[(substituted phenyl)alkyl]quinuclidines selectively increased action potential duration (Vaughan Williams class III activity). In the 2-substituted series some of the compounds both increased action potential duration and decreased conduction velocity (class I activity). For some of the 2-substituted quinuclidines, appropriate substitution of the phenyl ring was shown to be a requirement for significant class III electrophysiological activity. Selected compounds were efficacious in a programmed electrical stimulation model in the anesthetized dog.