Li Guiying, Jorgensen Morten, Campbell Brian M, Doller Dario
Discovery Chemistry & DMPK, Lundbeck Research USA, 215 College Rd, Paramus, NJ 07652, USA.
Curr Top Med Chem. 2016;16(29):3470-3526. doi: 10.2174/1568026616666160405113536.
In the last ~30 years, scientists have made great strides in understanding the biological function of group I metabotropic glutamate receptors (mGlu) in health and disease, as well as developing a broad array of potent and selective agents able to activate or inhibit these receptors. This article provides a comprehensive review of the most recent group I mGlu modulators published in patent and non-patent literatures from 2014 to May, 2015, including design, structure-activity relationship, in silico, in vitro and in vivo properties of key compounds. The current status of clinical mGlu5 negative allosteric modulators (NAMs) and the development of mGlu1 and mGlu5 PET ligands are also highlighted. While the therapeutic potential for group I mGlu modulating agents appears high, significant challenges remain. Strategies to reduce clinical development risks and mitigate important side effects, including psychotomimetic events observed with several mGlu5 NAMs and cellular toxicity associated with mGlu5 positive allosteric modulators (PAMs), while retaining therapeutic efficacy through approaches such as biased ligand signaling are discussed.
在过去约30年里，科学家们在了解I型代谢型谷氨酸受体（mGlu）在健康和疾病中的生物学功能，以及研发一系列能够激活或抑制这些受体的强效且选择性的药物方面取得了巨大进展。本文全面综述了2014年至2015年5月期间发表在专利和非专利文献中的最新I型mGlu调节剂，包括关键化合物的设计、构效关系、计算机模拟、体外和体内特性。还重点介绍了临床mGlu5负变构调节剂（NAMs）的现状以及mGlu1和mGlu5正电子发射断层扫描（PET）配体的研发情况。虽然I型mGlu调节剂的治疗潜力似乎很高，但仍存在重大挑战。文中讨论了降低临床开发风险和减轻重要副作用的策略，包括几种mGlu5 NAMs观察到的拟精神病事件以及与mGlu5正变构调节剂（PAMs）相关的细胞毒性，同时通过偏向配体信号传导等方法保持治疗效果。
