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Agonist Actions of "-Blockers" Provide Evidence for Two Agonist Activation Sites or Conformations of the Human ₁-Adrenoceptor

Institute of Cell Signalling, Medical School, Queen's Medical Centre, Nottingham, United Kingdom

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 ₁-adrenoceptor: 1) where classic agonists (catecholamines) and -antagonists act, and 2) where CGP 12177 is an agonist and relatively resistant to inhibition by -adrenoceptor antagonists. In the present study, we have used studies of cAMP response element-regulated gene transcription to confirm the presence of these two ₁-adrenoceptor sites/conformations and to provide strong evidence that a range of clinically used -adrenoceptor blockers (-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 -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 -blockers seen in the clinic may therefore be caused in part by these -blocker agonist responses and the differential activation of the two sites or conformations.

Address correspondence to: Professor S. J. Hill, Institute of Cell Signaling, Queen's Medical Centre, Nottingham NG7 2UH, UK. E-mail: stephen.hill{at}nottingham.ac.uk

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