Myocardial and local anesthetic actions of β-adrenergic receptor blocking drugs: Relationship to physicochemical properties

In 19 compoundsstudied, there was no simple relationship between β-blocking potency, lipoid solubility, pK a, or propensity for depressing myocardial contraction. No correlation existed between lipoid solubility and negative inotropism on isolated rabbit atria. Pronethalol and propranolol (CHCl 3/H 2O partition ratios: 15 and 34.5, respectively) showed strong local anesthetic effects (rabbit cornea test) while MJ-1999 and INPEA (CHCl 3/H 2O partition ratios: 0.03 and 1.29, respectively) were completely devoid of this action. That lipoid solubility is not solely involved, however, is evidenced by compound Kö-592 which has a partition ratio of 0.096, yet still has significant local anesthetic actions. The weak β-blocker (+)-propranolol showed almost the identical local anesthetic as the more potent racemate, suggesting a minimum of complementarity between this drug and the receptor system mediating local anesthesia. It also indicates that β-blocking potency per se is not involved in this effect. The (−)/(+) isomer ratios of activity ranged from 15 to 50 for myocardial β-blocking effects.