Inotropie and Chronotropic Effects of a Series of β-Adrenergic Blocking Drugs: Some Structure-Activity Relationships.

Summary The inotropic and chronotropic effects of 6 beta-adrenergic blocking drugs and their optical isomers were studied on isolated atrial preparations of the rabbit heart. The phenoxyisopropanolamine compound Ko−592 (1- (3-methylphenoxy) −3-iso-propylaminopropanol) was the most potent beta-adrenolytic compound. DCI and dl-pro-pranolol were only slightly less potent; however, pronethalol and 2 methanesulfonanilide substituted compounds (MJ-1998 and MJ-1999) showed weaker actions. The d- isomers of pronethalol, propranolol, and MJ-1999 were approximately 7-11 times weaker as beta-blochers than their corresponding racemates. The l- isomers of pronethalol and MJ-1999 were 2-3 times more potent than the dl-isomers. The 2 naphthyl compounds (pro-pranolol and pronethalol and their isomers) produced significant depression of myocardial contraction and electrical properties (refractory period and excitability). In equal or higher concentrations, MJ-1998 and MJ-1999 showed no significant effect on the electrically driven atria. DCI produced a significant and sustained increase in force of contraction in a concentration of 1.35 × 10-6 M. A higher concentration (1.35 × 10-4 M) produced a transient increase in force of contraction followed by a rapid decrease leading to asystole. In a concentration of 1.35 × 10-5 M, only dl- and d-propranolol produced a significant decrease in heart rate of spontaneously beating right atrial preparations. DCI produced a significant increase in rate. On the basis of the compounds studied, there does not appear to be any simple interrelationship between (a) chemical structure, (b) direct inotropic and chronotropic effects, (c) beta-blocking potency, and (d) ability to depress the electrical properties of the myocardium.