Molecular Pharmacology, Vol 12, 203-207, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Inhibition of Isoproterenol Activation of Adenylate Cyclase by Metoprolol, Oxprenolol, and the para Isomer of Oxprenolol

¹ Research Department, Pharmaceuticals Division, Ciba-Geigy Corporation, Ardsley, New York 10502

The beta adrenergic blocking agents metoprolol, oxprenolol, and the para isomer of oxprenolol were evaluated as inhibitors of isoproterenol activation of adenylate cyclase (EC 4.6.1.1) in membrane preparations from dog heart and liver. Metoprolol, like practolol, was selective, since both drugs inhibited activation of the heart enzyme 10 times more effectively than the liver enzyme. However, metoprolol was considerably more potent than practolol, although it was less active than propranolol. Oxprenolol was a highly effective inhibitor in these systems, comparable in potency to propranolol. Oxprenolol, like propranolol, was a nonspecific beta blocker, since these drugs inhibited both heart and liver enzyme systems with the same potency. In contrast, the para isomer of oxprenolol was beta₁ selective, although it was considerably less potent than oxprenolol. The biochemical data are consistent with the pharmacological effects of these drugs and add further support to the proposed role of the adenylate cyclase system in the molecular mechanisms associated with beta adrenergic stimulation and inhibition.

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ACKNOWLEDGMENT We would like to express our appreciation to Dr. William D. Cash for valuable advice during the course of this work.