PT - JOURNAL ARTICLE AU - Anish A. Konkar AU - Zhengxian Zhu AU - James G. Granneman TI - Aryloxypropanolamine and Catecholamine Ligand Interactions with the β<sub>1</sub>-Adrenergic Receptor: Evidence for Interaction with Distinct Conformations of β<sub>1</sub>-Adrenergic Receptors DP - 2000 Sep 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 923--932 VI - 294 IP - 3 4099 - http://jpet.aspetjournals.org/content/294/3/923.short 4100 - http://jpet.aspetjournals.org/content/294/3/923.full SO - J Pharmacol Exp Ther2000 Sep 01; 294 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