Anomalous behavior of CGP 12177A on beta 1-adrenergic receptors

J Recept Signal Transduct Res. Jan-Mar 1996;16(1-2):1-23. doi: 10.3109/10799899609039938.


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.

MeSH terms

  • 1-Methyl-3-isobutylxanthine / pharmacology
  • Adenylyl Cyclases / metabolism
  • Adrenergic beta-Agonists / pharmacology*
  • Adrenergic beta-Antagonists / pharmacology*
  • Animals
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Colforsin / pharmacology
  • Cricetinae
  • Cyclic AMP / metabolism
  • Dose-Response Relationship, Drug
  • GTP-Binding Proteins / metabolism
  • Humans
  • Isoproterenol / pharmacology
  • Propanolamines / administration & dosage
  • Propanolamines / pharmacology*
  • Propranolol / pharmacology
  • Rats
  • Receptors, Adrenergic, beta / drug effects
  • Receptors, Adrenergic, beta / metabolism*
  • Stereoisomerism
  • Transfection
  • Zinc / pharmacology


  • Adrenergic beta-Agonists
  • Adrenergic beta-Antagonists
  • Propanolamines
  • Receptors, Adrenergic, beta
  • Colforsin
  • Propranolol
  • Cyclic AMP
  • GTP-Binding Proteins
  • Adenylyl Cyclases
  • Zinc
  • Isoproterenol
  • CGP 12177
  • 1-Methyl-3-isobutylxanthine