title: Aryloxypropanolamine and catecholamine ligand interactions with the beta(1)-adrenergic receptor: evidence for interaction with distinct conformations of beta(1)-adrenergic receptors.
abstract: 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.
authors.affiliation: Cellular and Clinical Neurobiology Program, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Konkar
authors.forename: Z
authors.initials: Z
authors.lastname: Zhu
authors.forename: J G
authors.initials: JG
authors.lastname: Granneman
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D018674:Adrenergic Antagonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002395:Catecholamines / Q000494:pharmacology*; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D008024:Ligands; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*; D011487:Protein Conformation; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D014162:Transfection
chemical_list: D018674:Adrenergic Antagonists; D000318:Adrenergic beta-Agonists; D001562:Benzimidazoles; D002395:Catecholamines; C412890:LY 362884; D008024:Ligands; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D009536:Niacinamide; D000262:Adenylyl Cyclases; C033394:CGP 12177