Structure-activity relationships of beta-adrenergic receptor-coupled adenylate cyclase: implications of a redox mechanism for the action of agonists at beta-adrenergic receptors.
The present studies have tested the hypothesis that agonists at beta-adrenergic receptors activate the beta-receptors by reducing them. This was examined by analyzing the interactions of 41 beta-agonists and antagonists with the receptors. The structural features which determined binding affinity (KD) were shown to be distinct from those which determined intrinsic, activity (IA). The IA was shown to be related to the oxidation-reduction properties which were determined primarily by the nature of the substituents on the phenyl ring. Thus, the parent compound phenylethanolamine, having no phenolic substituent, acted as an antagonist (IA = 0) and was also redox inactive. All of the antagonists tested (19) exhibited EP (peak potential for the first oxidative wave) values greater than 0.75 V, suggesting that they were difficult to oxidize. Agonists, however, exhibited a wide range of EP (0.25-0.7 V) with values lower than those of the antagonists. The agonists tested include catecholamines, catecholamine analogs bearing meta-substituted amino functionalities (such as amino, methylamino, formanilide, sulfonamide, urea, and carbamate), resorcinol, and hydroxymethyl congeners. It is proposed that the oxidizing tendency of the substituent on the phenyl ring is one of the factors that influences IA. To test the hypothesis further, we electrolytically oxidized isoproterenol to adrenochrome or to the o-quinone intermediate and tested for activity. The 4e-, 4H+-oxidation product adrenochrome did not bind to or stimulate adenylate cyclase, suggesting that the reducing ability to isoproterenol is important for its agonistic activity. A cyclic redox mechanism for the action of agonists at beta-adrenergic receptors is presented. We propose that agonist are electron donors. Their interactions with receptors result in reduction leading to activation of the receptors.
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000378:metabolism*; D000319:Adrenergic beta-Antagonists / Q000378:metabolism; D000323:Adrenochrome / Q000378:metabolism; D000818:Animals; D001001:Anura; D016227:Benzoquinones; D002395:Catecholamines / Q000378:metabolism; D002853:Chromatography, Liquid; D004082:Dihydroalprenolol / Q000378:metabolism; D004563:Electrochemistry; D004910:Erythrocyte Membrane / Q000378:metabolism; D007545:Isoproterenol / Q000378:metabolism; D007700:Kinetics; D010084:Oxidation-Reduction; D011809:Quinones / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D016227:Benzoquinones; D002395:Catecholamines; D011809:Quinones; D011943:Receptors, Adrenergic, beta; C004532:quinone; D004082:Dihydroalprenolol; D000323:Adrenochrome; D000262:Adenylyl Cyclases; D007545:Isoproterenol