Molecular Pharmacology, Vol 12, 693-700, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Hydroxybenzylpindolol and Hydroxybenzylpropranolol: Partial Beta Adrenergic Agonists of Adenylate Cyclase in the Rat Adipocyte

¹ Membrane Regulation Section, Laboratory of Nutrition and Endocrinology, National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Bethesda, Maryland 20014
² Division of Biological and Medical Sciences, Brown University, Providence, Rhode Island 02912

Hydroxybenzylpindolol stimulates adenylate cyclase activity in purified plasma membranes from the rat adipocyte. The intrinsic activity of hydroxybenzylpindolol is about 35% less than that of isoproterenol and is inhibited stereoselectively by (-)-propranolol. Thus hydroxybenzylpindolol is both a partial agonist and an antagonist of catecholamine activation of adenylate cyclase. Hydroxybenzylpropranolol, the corresponding derivative of the antagonist propranolol, is also a partial agonist, although considerably weaker than hydroxybenzylpindolol and about equivalent in intrinsic activity to pindolol. Based on the relative inhibitory effects of propranolol, the affinities of the beta receptor for hydroxybenzylpindolol and hydroxybenzylpropranolol are equivalent but are about 10 times that of pindolol or propranolol and 25-40 times that of isoproterenol. The stimulatory effects of the partial agonists are mediated by the same guanine nucleotide regulatory process observed with catecholamines. The potency and intrinsic activity exhibited by hydroxybenzylpindolol on adenylate cyclase in isolated membranes correlated with its stimulatory effect on cyclic 3',5'-AMP accumulation and lipolysis in intact fat cells. Hydroxybenzylpindolol increased lipolysis and cyclic AMP accumulation by intact fat cells at a concentration of 10 nM, while isoproterenol was without effect at this concentration. However, at higher concentrations hydroxybenzylpindolol gave a maximal activation of either parameter which was about one-third that due to isoproterenol.