Photoaffinity label for the beta-adrenergic receptor: synthesis and effects on isoproterenol-stimulated adenylate cyclase.

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Abstract
An azide derivative of the .beta.-adrenergic antagonist acebutolol [RS-1-(2-acetyl-4-amino)-2-hydroxy-3-isopropylaminopropane], was synthesized and its effect examined on the isoproterenol-stimulated adenylate cyclase [ATP pyrophosphate-lyase (cyclizing); EC 4.6.1.1] activity of rat reticulocytes. It behaved as an effective competitive antagonist (Kd = 2 .times. 10-7 M) prior to photolysis. When the reticulocyte preparation pretreated with acebutolol azide was photolyzed, a noncompetitive inhibition of isoproterenol-stimulated adenylate cyclase was obtained. Photolysis of the azide derivative in buffer alone did not convert it to a product of higher affinity. Labeling of the .beta.-adrenergic receptor appeared to be irreversible; multiple washings could not reverse the inhibition produced during photolysis with the label but washing would completely reverse the antagonism produced by the same concentration of label prior to photolysis. The effect appears to be specific for the .beta.-adrenergic receptor because the inhibition could be blocked stereoselectively by propranolol and there was no inhibition of fluoride- or GMP-P(NH)P-stimulated adenylate cyclase. No effect was observed on the glucagon-mediated stimulation of adenylate cyclase of liver membranes; the catecholamine response in the same membranes was inhibited.

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