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

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Phillips GB, Morgan TK Jr, Lumma WC Jr, Gomez RP, Lind JM, Lis R, Argentieri T, Sullivan ME

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

J Med Chem. 1992 Feb 21;35(4):743-50.

PubMed ID

1347318 [ View in PubMed

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Abstract

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).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Sotalol	Beta-1 adrenergic receptor	IC 50 (nM)	9000	N/A	N/A	Details