RT Journal Article SR Electronic T1 Aryloxypropanolamine and Catecholamine Ligand Interactions with the β1-Adrenergic Receptor: Evidence for Interaction with Distinct Conformations of β1-Adrenergic Receptors JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 923 OP 932 VO 294 IS 3 A1 Anish A. Konkar A1 Zhengxian Zhu A1 James G. Granneman YR 2000 UL http://jpet.aspetjournals.org/content/294/3/923.abstract AB Pharmacological responses to aryloxypropanolamines were examined in cells expressing rat or human β1-adrenergic receptors (ARs) using adenylyl cyclase assays. The aryloxypropanolamines CGP 12177 and LY 362884, originally developed as β3-AR agonists, were found to stimulate the β1-AR. Interestingly, both CGP 12177 and LY 362884 exhibited an anomalous biphasic effect on β1-AR. Low concentrations of either CGP 12177 or LY 362884 potently blocked isoproterenol-induced stimulation of β1-AR, whereas higher concentrations of these compounds stimulated the β1-AR. The unusual interaction of these aryloxypropanolamine ligands with the β1-AR was further characterized using β-AR antagonists. Activation of β1-AR by CGP 12177 or LY 362884 was observed to be significantly more resistant to blockade by β-AR antagonists compared with activation by catecholamines. These results suggest that catecholamines and aryloxypropanolamines interact with distinct active conformations of the β1-AR: a state that is responsive to catecholamines and is blocked with high affinity by CGP 12177 and LY 362884, and a novel state that is activated by aryloxypropanolamines but is resistant to blockade by standard β-AR antagonists. Moreover, dependence of antagonist affinity on agonist structure is unprecedented, and its implications on the use of β-AR agonists such as CGP 12177 in receptor classification are discussed. The American Society for Pharmacology and Experimental Therapeutics