Abstract
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.
Footnotes
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Send reprint requests to: Dr. James G. Granneman, Parke-Davis Pharmaceutical Research, 2800 Plymouth Rd., Ann Arbor, MI 48201. E-mail: james.granneman{at}wl.com orjgranne{at}med.wayne.edu
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↵1 This work was supported by United States Public Health Service Grant DK46339.
- Abbreviations:
- AR
- adrenergic receptor
- CHO
- Chinese hamster ovary
- Received February 22, 2000.
- Accepted May 9, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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