title: Anomalous behavior of CGP 12177A on beta 1-adrenergic receptors.
abstract: CGP 12177A originally was developed as a hydrophilic antagonist to detect cell surface beta 1- and beta 2-adrenergic receptors, and subsequently was found to be a partial agonist for the atypical or beta 3-adrenergic receptor. Using hamster cells stably expressing either the human beta 1-, human beta 2- or rat beta 1-adrenergic receptor, we found that CGP 12177A behaved as an agonist of beta 1-adrenergic receptors. Whereas at low concentrations, CGP 12177a behaved as an antagonist and inhibited isoproterenol stimulation of adenylyl cyclase activity, at higher concentrations, it stimulated a response even in the absence of isoproterenol. The agonistic properties of CGP 12177A were positively correlated with the level of beta 1-adrenergic receptor expression. Thus, at low receptor of densities, CGP 12177A behaved as a weak, partial agonist whereas as high receptor densities, the drug was a full agonist. At similar high densities of the beta 2-adrenergic receptor, CGP 12177A acted only as a partial agonist. Competition binding studies to membranes from cells expressing beta 1-adrenergic receptors indicated that approximately 90% of the receptors were in a high affinity, guanine nucleotide-insensitive state for CGP 12177A whereas approximately 10% of the receptors were in a lower affinity, guanine nucleotide-sensitive state for CGP 12177A. We propose that the latter receptors are precoupled to stimulatory G proteins and recognize CGP 12177A as an agonist whereas the high affinity, uncoupled receptors recognize CGP 12177A as an antagonist.
authors.affiliation: Membrane Biochemistry Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Pak
authors.forename: P H
authors.initials: PH
authors.lastname: Fishman
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D011412:Propanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D013237:Stereoisomerism; D014162:Transfection; D015032:Zinc / Q000494:pharmacology
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D011433:Propranolol; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D015032:Zinc; D007545:Isoproterenol; C033394:CGP 12177; D015056:1-Methyl-3-isobutylxanthine