Vanderbilt Center for Neuroscience Drug Discovery , Vanderbilt University Medical Center , Nashville , Tennessee 37232 , United States.
Department of Pharmacology , Vanderbilt University School of Medicine , Nashville , Tennessee 37232 , United States.
ACS Chem Neurosci. 2019 Mar 20;10(3):1025-1034. doi: 10.1021/acschemneuro.8b00481. Epub 2018 Oct 17.
The muscarinic acetylcholine receptor (mAChR) subtype 5 (M) was the most recent mAChR to be cloned and has since emerged as a potential therapeutic target for a number of indications. Early studies with knockout animals have provided clues to the receptor's role in physiological processes related to Alzheimer's disease, schizophrenia, and addiction, and until recently, useful subtype-selective tools to further probe the pharmacology of M have remained elusive. Small-molecule allosteric modulators have since gained traction as a means by which to selectively examine muscarinic pharmacology. This review highlights the discovery and optimization of M positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs).
毒蕈碱型乙酰胆碱受体（mAChR）亚型 5（M）是最近被克隆的 mAChR，已成为多种适应症的潜在治疗靶点。早期对基因敲除动物的研究为该受体在与阿尔茨海默病、精神分裂症和成瘾相关的生理过程中的作用提供了线索，直到最近，仍然缺乏有用的亚型选择性工具来进一步探究 M 的药理学。小分子变构调节剂已成为选择性检查毒蕈碱药理学的一种手段。本综述重点介绍了 M 正变构调节剂（PAMs）和负变构调节剂（NAMs）的发现和优化。
