Kopin A S, McBride E W, Gordon M C, Quinn S M, Beinborn M
Division of Gastroenterology and GRASP Digestive Disease Center, Tupper Research Institute, New England Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA.
Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):11043-8. doi: 10.1073/pnas.94.20.11043.
The brain cholecystokinin-B/gastrin receptor (CCK-BR) is a major target for drug development because of its postulated role in modulating anxiety, memory, and the perception of pain. Drug discovery efforts have resulted in the identification of small synthetic molecules that can selectively activate this receptor subtype. These drugs include the peptide-derived compound PD135,158 as well as the nonpeptide benzodiazepine-based ligand, L-740,093 (S enantiomer). We now report that the maximal level of receptor-mediated second messenger signaling that can be achieved by these compounds (drug efficacy) markedly differs among species homologs of the CCK-BR. Further analysis reveals that the observed differences in drug efficacy are in large part explained by single or double aliphatic amino acid substitutions between respective species homologs. This interspecies variability in ligand efficacy introduces the possibility of species differences in receptor-mediated function, an important consideration when selecting animal models for preclinical drug testing. The finding that even single amino acid substitutions can significantly affect drug efficacy prompted us to examine ligand-induced signaling by a known naturally occurring human CCK-BR variant (glutamic acid replaced by lysine in position 288; 288E --> K). When examined using the 288E --> K receptor, the efficacies of both PD135,158 and L-740, 093 (S) were markedly increased compared with values obtained with the wild-type human protein. These observations suggest that functional variability resulting from human receptor polymorphisms may contribute to interindividual differences in drug effects.
脑胆囊收缩素 - B/胃泌素受体（CCK - BR）是药物研发的主要靶点，因为它在调节焦虑、记忆和痛觉方面具有假定作用。药物研发工作已导致鉴定出能够选择性激活该受体亚型的小分子合成化合物。这些药物包括肽衍生化合物PD135,158以及基于非肽苯二氮䓬的配体L - 740,093（S对映体）。我们现在报告，这些化合物所能实现的受体介导的第二信使信号传导的最大水平（药物疗效）在CCK - BR的物种同源物之间存在显著差异。进一步分析表明，观察到的药物疗效差异在很大程度上是由各个物种同源物之间的单或双脂肪族氨基酸取代所解释的。配体疗效的这种种间变异性引入了受体介导功能存在物种差异的可能性，这是在选择临床前药物测试的动物模型时的一个重要考虑因素。即使单个氨基酸取代也能显著影响药物疗效这一发现促使我们研究一种已知的天然存在的人类CCK - BR变体（第288位谷氨酸被赖氨酸取代；288E→K）的配体诱导信号传导。当使用288E→K受体进行检测时，与野生型人类蛋白相比，PD135,158和L - 740,093（S）的疗效均显著增加。这些观察结果表明，人类受体多态性导致的功能变异性可能导致药物效应的个体差异。
