Structure-activity relationship for antiarrhytmic actions of β-receptor blocking drugs

Abstract

Antiarrhythmic activity of the three tolyloxypropanolamine derivatives, Kö 589, Kö 592 and Kö 612, against ventricular arrhytmias elicited by epinephrine or ouabain was investigated in the dog heart-lung preparation. Kö 589, Kö 592 and Kö 612 all prevented the development of ventricular fibrillation and multifocal ventricular tachycardia elicited by the halothane-epinephrine and the halothane-epinephrine-pressor challenge respectively. Kö 592 was more than twice as active as the other two drugs in this respect. Only Kö 592 was able to suppress effectively the ouabain-induced ventricular arrhythmias. The local anesthetic activity of these drugs was tested on the rabbit cornea and in the guinea pig skin; Kö 592 and Kö 612 were more active than Kö 589 in producing topical as well as infiltration anesthesia. A correlation of the structure-activity relationship suggests that changing the position of the methyl group in the benzene ring from meta to either para or ortho positions decreases both the antiadrenergic and the antidigitalis but not the local anesthetic activity of these agents. Substitution of the methyl group in meta position (Kö 592) yields the most active compound for both the β-adrenoreceptor blocking and antidigitalis activities. It is well known that the dose of the beta adrenergic blocking agents to suppress digitalis-induced arrhythmias is usually larger than that necessary for protection against epinephrine-induced arrhythmias. Separation of the antiadrenergic and antidigitalis potencies can be increased even further by moving the methyl group to either meta or para positions in the benzene ring of these phenoxypropanolamine derivatives.