Quantitative structure-activity studies of beta-adrenoceptor blocking drugs to decrease ventricular arrhythmias in guinea pigs.

Abstract

The correlations between the physicochemical properties (n-octanol-buffer partition coefficients, P) of two series of N-alkylated and ring alkylated beta-adrenoceptor blocking phenoxypropanolamines and their antiarrhythmic activities were studied. For this purpose dose-response curves of the influence on the ventricular arrhythmia threshold (VAT) and on heart rate (HR) were determined in the anaesthetized guinea pig. The degree of N-alkylation correlated with the potency of the drugs to raise VAT and to lower HR. Intraventricular conduction was likewise depressed. Increasing ring alkylation did not consistently further increase biological activity. The combined data from series of drugs showed statistically significant parabolic correlations between hydrophobicity (log P' for pH 7.4) and the biological responses. It is concluded that the nonspecific antiarrhythmic and negative chronotropic activity of the investigated beta-adrenoceptor blocking drugs largely depend on their lipophilic properties. In addition steric and pharmacokinetic factors may be operative.