Pak M D, Fishman P H
Membrane Biochemistry Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Recept Signal Transduct Res. 1996 Jan-Mar;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.
CGP 12177A最初是作为一种亲水性拮抗剂开发的，用于检测细胞表面的β1和β2肾上腺素能受体，随后发现它是一种非典型或β3肾上腺素能受体的部分激动剂。使用稳定表达人β1、人β2或大鼠β1肾上腺素能受体的仓鼠细胞，我们发现CGP 12177A表现为β1肾上腺素能受体的激动剂。在低浓度时，CGP 12177a表现为拮抗剂，抑制异丙肾上腺素对腺苷酸环化酶活性的刺激，而在高浓度时，即使在没有异丙肾上腺素的情况下，它也能刺激反应。CGP 12177A的激动特性与β1肾上腺素能受体的表达水平呈正相关。因此，在低密度受体时，CGP 12177A表现为弱的部分激动剂，而在高密度受体时，该药物是完全激动剂。在类似的β2肾上腺素能受体高密度时，CGP 12177A仅作为部分激动剂起作用。对表达β1肾上腺素能受体的细胞的膜进行的竞争结合研究表明，大约90%的受体对CGP 12177A处于高亲和力、鸟嘌呤核苷酸不敏感状态，而大约10%的受体对CGP 12177A处于低亲和力、鸟嘌呤核苷酸敏感状态。我们提出，后一种受体与刺激性G蛋白预偶联，并将CGP 12177A识别为激动剂，而高亲和力、未偶联的受体将CGP 12177A识别为拮抗剂。
