Anomalous Behavior of CGP 12177A ON β2-Adrenergic Receptors

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Abstract
CGP 12177A originally was developed as a hydrophilic antagonist to detect cell surface β1- and β2-adrenergic receptors, and sub-sequently was found to be a partial agonist for the atypical or β3-adrenergic receptor. Using hamster cells stably expressing either the human β1-, human β2- or rat β1-adrenergic receptor, we found that CGP 12177A behaved as an agonist for β1-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 β1-adrenergic receptor expression. Thus, at low receptor 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 β2-adrenergic receptor, CGP 12177A acted only as a partial agonist. Competition binding studies to membranes from cells expressing β1-adrenergic receptors indicated that -90% of the receptors were in a high affinity, guanine nucleotide-insensitive state for CGP 12177A whereas -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.