Aryloxypropanolamine and catecholamine ligand interactions with the beta(1)-adrenergic receptor: Evidence for interaction with distinct conformationsof beta(1)-adrenergic receptors

Pharmacological responses to aryloxypropanolamines were examined in cells e xpressing rat or human beta(1)-adrenergic receptors (ARs) using adenylyl cy clase assays. The aryloxypropanolamines CGP 12177 and LY 362884, originally developed as beta(3)-AR agonists, were found to stimulate the beta(1)-AR, Interestingly, both CGP 12177 and LY 362884 exhibited an anomalous biphasic effect on beta(1)-AR, Low concentrations of either CGP 12177 or LY 362884 potently blocked isoproterenol-induced stimulation of beta(1)-AR, whereas h igher concentrations of these compounds stimulated the beta(1)-AR. The unus ual interaction of these aryloxypropanolamine ligands with the beta(1)-AR w as further characterized using beta-AR antagonists. Activation of beta(1)-A R by CGP 12177 or LY 362884 was observed to be significantly more resistant to blockade by beta-AR antagonists compared with activation by catecholami nes. These results suggest that catecholamines and aryloxypropanolamines in teract with distinct active conformations of the beta(1)-AR: a state that i s responsive to catecholamines and is blocked with high affinity by CGP 121 77 and LY 362884, and a novel state that is activated by aryloxypropanolami nes but is resistant to blockade by standard beta-AR antagonists. Moreover, dependence of antagonist affinity on agonist structure is unprecedented, a nd its implications on the use of beta-AR agonists such as CGP 12177 in rec eptor classification are discussed.