Agonist actions of "beta-blockers" provide evidence for two agonist activation sites or conformations of the human beta1-adrenoceptor.

Previous work with 4-[3-[(1,1-dimethylethyl)amino]2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one (CGP 12177) has led to the suggestion that there are two different agonist conformations of the human beta1-adrenoceptor: 1) where classic agonists (catecholamines) and beta-antagonists act, and 2) where CGP 12177 is an agonist and relatively resistant to inhibition by beta-adrenoceptor antagonists. In the present study, we have used studies of cAMP response element-regulated gene transcription to confirm the presence of these two beta1-adrenoceptor sites/conformations and to provide strong evidence that a range of clinically used beta-adrenoceptor blockers (beta-blockers) exhibit differential agonists and/or antagonist actions at the two sites. [2-(3-Carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1-methyl-4-trifluormethyl-2-imidazolyl)-phenoxy]-2-propanolmethanesulphonate (CGP 20712A) and atenolol act as classic antagonists at the catecholamine binding site but have much lower affinity for the secondary CGP 12177 site. CGP 12177 and carvedilol are potent antagonists at the catecholamine site but mediate substantial agonist actions on gene transcription via the secondary antagonist-resistant site at higher concentrations. Agonist effects of beta-blockers are not, however, confined to this secondary site, and we show that some (particularly acebutolol and labetolol) act primarily via the catecholamine site, whereas others (pindolol and alprenolol) can stimulate both. The different responses to beta-blockers seen in the clinic may therefore be caused in part by these beta-blocker agonist responses and the differential activation of the two sites or conformations.