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Vol. 294, Issue 3, 923-932, September 2000

Aryloxypropanolamine and Catecholamine Ligand Interactions with the beta 1-Adrenergic Receptor: Evidence for Interaction with Distinct Conformations of beta 1-Adrenergic Receptors1

Anish A. Konkar, Zhengxian Zhu and James G. Granneman

Cellular and Clinical Neurobiology Program, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan

Pharmacological responses to aryloxypropanolamines were examined in cells expressing rat or human beta 1-adrenergic receptors (ARs) using adenylyl cyclase 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 higher concentrations of these compounds stimulated the beta 1-AR. The unusual interaction of these aryloxypropanolamine ligands with the beta 1-AR was further characterized using beta -AR antagonists. Activation of beta 1-AR by CGP 12177 or LY 362884 was observed to be significantly more resistant to blockade by beta -AR antagonists compared with activation by catecholamines. These results suggest that catecholamines and aryloxypropanolamines interact with distinct active conformations of the beta 1-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 beta -AR antagonists. Moreover, dependence of antagonist affinity on agonist structure is unprecedented, and its implications on the use of beta -AR agonists such as CGP 12177 in receptor classification are discussed.

1 This work was supported by United States Public Health Service Grant DK46339.

0022-3565/00/2943-0923$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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