Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, and Department of Pharmacology, Monash University, Parkville 3052, Australia; email:
School of Pharmacy, Fudan University, Shanghai 201203, China.
Annu Rev Pharmacol Toxicol. 2020 Jan 6;60:89-107. doi: 10.1146/annurev-pharmtox-010919-023301. Epub 2019 Aug 27.
Recent advances in our understanding of the structure and function of class B G protein-coupled receptors (GPCRs) provide multiple opportunities for targeted development of allosteric modulators. Given the pleiotropic signaling patterns emanating from these receptors in response to a variety of natural agonist ligands, modulators have the potential to sculpt the responses to meet distinct needs of different groups of patients. In this review, we provide insights into how this family of GPCRs differs from the rest of the superfamily, how orthosteric agonists bind and activate these receptors, the potential for allosteric modulators to interact with various regions of these targets, and the allosteric influence of endogenous proteins on the pharmacology of these receptors, all of which are important considerations when developing new therapies.
近年来，我们对 B 类 G 蛋白偶联受体（GPCR）的结构和功能的理解取得了进展，为变构调节剂的靶向开发提供了多种机会。鉴于这些受体对各种天然激动剂配体的反应产生的多效性信号模式，调节剂有可能塑造反应，以满足不同患者群体的不同需求。在这篇综述中，我们深入了解了这个 GPCR 家族与超家族的其他成员有何不同，变构激动剂如何结合并激活这些受体，变构调节剂与这些靶标的不同区域相互作用的潜力，以及内源性蛋白对这些受体药理学的变构影响，所有这些都是开发新疗法时需要考虑的重要因素。
