Synthesis, cardiac electrophysiology, and .beta.-blocking activity of novel arylpiperazines with potential as class II/III antiarrhythmic agents

• Published in: Journal of medicinal chemistry Vol. 35; no. 4; pp. 743 - 750
• Main Authors: Phillips, Gary B, Morgan, Thomas K, Lumma, William C, Gomez, Robert P, Lind, Joan M, Lis, Randall, Argentieri, Thomas, Sullivan, Mark E
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.02.1992
• Subjects: Action Potentials - drug effects; Adrenergic beta-Antagonists - chemical synthesis; Adrenergic beta-Antagonists - pharmacology; Adrenergic beta-Antagonists - therapeutic use; Animals; Anti-Arrhythmia Agents - chemical synthesis; Anti-Arrhythmia Agents - pharmacology; Anti-Arrhythmia Agents - therapeutic use; Arrhythmias, Cardiac - drug therapy; Arrhythmias, Cardiac - etiology; Benzamides - chemical synthesis; Benzamides - pharmacology; Benzamides - therapeutic use; Binding, Competitive; Dogs; Electric Stimulation; Electrophysiology; Epinephrine; Heart - drug effects; Heart - physiology; Molecular Structure; Piperazines - chemical synthesis; Piperazines - pharmacology; Piperazines - therapeutic use; Purkinje Fibers - drug effects; Purkinje Fibers - physiology; Receptors, Adrenergic, beta - metabolism; Sotalol - pharmacology; Sotalol - therapeutic use; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00082a016

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).