Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors.
Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors.
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DOI：
10.1021/acs.chemrev.5b00656
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发表时间：
2016-06-08
期刊：
影响因子：
62.1
通讯作者：
Conn PJ
中科院分区：
文献类型：
--
作者：
Lindsley CW;Emmitte KA;Hopkins CR;Bridges TM;Gregory KJ;Niswender CM;Conn PJ
gpcr的变构调节开启了一个基础和转化发现的新时代，充满了治疗的希望，但也充满了警告。变构配体稳定了GPCR的独特构象，提供了全新的受体，能够产生新的药理学，前所未有的亚型选择性和独特的信号偏倚。这篇综述提供了GPCR变构药理学、药物化学、药物代谢的基础知识的全面概述，并验证了解决每个主要挑战和警告的方法。然后，本文将重点聚焦于代谢性谷氨酸受体亚型1-5和7 （mGlu 1-57）变构配体的发现方面的最新进展，重点介绍了关键概念（“分子开关”、信号偏偏、异源二聚体）和实际解决方案，以促进工具化合物和临床候选药物的开发。文章最后介绍了其他gpcr的变构配体的最新进展和内源性变构调节剂的新数据。
Allosteric modulation of GPCRs has initiated a new era of basic and translational discovery, filled with therapeutic promise yet fraught with caveats. Allosteric ligands stabilize unique conformations of the GPCR that afford fundamentally new receptors, capable of novel pharmacology, unprecedented subtype selectivity, and unique signal bias. This review provides a comprehensive overview of the basics of GPCR allosteric pharmacology, medicinal chemistry, drug metabolism, and validated approaches to address each of the major challenges and caveats. Then, the review narrows focus to highlight recent advances in the discovery of allosteric ligands for metabotropic glutamate receptor subtypes 1–5 and 7 (mGlu 1–57) highlighting key concepts (“molecular switches”, signal bias, heterodimers) and practical solutions to enable the development of tool compounds and clinical candidates. The review closes with a section on late-breaking new advances with allosteric ligands for other GPCRs and emerging data for endogenous allosteric modulators.