SYNTHESIS, CARDIAC ELECTROPHYSIOLOGY, AND BETA-BLOCKING ACTIVITY OF NOVEL ARYLPIPERAZINES WITH POTENTIAL AS CLASS II/III ANTIARRHYTHMIC AGENTS

A series of novel arylpiperazines have been prepared in an attempt to incorporate both class II (beta-receptor blocking) and class III antiarrhythmic properties in a single molecule. The key step in the preparation of the new compounds involves a regioselective heterocyclic ring formation. All but four compounds significantly prolonged action potential duration in canine cardiac Purkinje fibers (class III activity). All but one of the compounds demonstrated beta-receptor affinity in a competitive binding assay and three had beta(1)-receptor selectivity. Compared to sotalol, a reference class II/III agent, arylpiperazine 7a (4-[(methylsulfonyl)amino]-N-[(4-phenylpiperazin-2-yl)methyl]benzamide) demonstrated beta(1)-selectivity and was 1 order of magnitude more potent in the in vitro class III and the beta(1)-receptor screens. Compound 7a was evaluated further and found to be effective in preventing programmed electrical stimulation-induced arrhythmias in conscious dogs (class III activity) and against epinephrine-induced arrhythmias in halothane anesthetized dogs (class II activity).