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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Identification of a series of CCK-2 receptor nonpeptide agonists: Sensitivity to stereochemistry and a receptor point mutation.
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Identification of a series of CCK-2 receptor nonpeptide agonists: Sensitivity to stereochemistry and a receptor point mutation.

机译：鉴定一系列CCK-2受体非肽激动剂：对立体化学的敏感性和受体点突变。

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摘要

The search for small-molecule drugs that act at peptide hormone receptors has resulted in the identification of a wide variety of antagonists. In contrast, the discovery of nonpeptide agonists has been far more elusive. We have used a constitutively active mutant of the cholecystokinin 2 receptor (CCK-2R) as a sensitive screen to detect ligand activity. Functional assessment of structural analogs of the prototype CCK-2R antagonist, L-365,260 [3R-N- (2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N'-(3-meth ylphenyl)urea], resulted in the identification of a series of agonists. Each of the active molecules is an S enantiomer, whereas the corresponding R stereoisomers have little or no activity. Further in vitro and in vivo assessment at the wild-type receptor indicated that efficacy of the two most active ligands approached that of the endogenous hormone. The function of selected R and S enantiomers was differentially sensitive to a point mutation, N353L, within the putative CCK-2R ligand pocket. The results of this study highlight the potential of constitutively active receptors as drug screening tools and the interdependence of ligand stereochemistry and receptor conformation in defining drug efficacy.
机译：对作用于肽激素受体的小分子药物的研究已导致鉴定出多种拮抗剂。相反，非肽激动剂的发现要难得多。我们已使用胆囊收缩素2受体（CCK-2R）的组成型活性突变体作为敏感筛选来检测配体活性。原型CCK-2R拮抗剂L-365,260 [3R-N-（2,3-二氢-1-甲基-2-氧代-5-苯基-1H-1,4-苯并二氮杂-3-基] -N'-（3-甲基基苯基）脲]导致鉴定出一系列激动剂。每个活性分子是S对映异构体，而相应的R立体异构体几乎没有或没有活性。对野生型受体的进一步体外和体内评估表明，两种活性最高的配体的功效接近内源激素的功效。选定的R和S对映异构体的功能对假定的CCK-2R配体口袋中的点突变N353L敏感。这项研究的结果突出了组成性活性受体作为药物筛选工具的潜力以及配体立体化学和受体构象在定义药物功效中的相互依赖性。

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