Ligand bias at the muscarinic acetylcholine receptor family: Opportunities and challenges

IF 4.6 2区 医学 Q1 NEUROSCIENCES
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Abstract

Muscarinic acetylcholine receptors (mAChRs) are G protein-coupled receptors (GPCRs) that are activated by the endogenous neurotransmitter, acetylcholine (ACh). Disruption of mAChR signalling has been associated with a variety of neurological disorders and non-neurological diseases. Consequently, the development of agonists and antagonists of the mAChRs has been a major avenue in drug discovery. Unfortunately, mAChR ligands are often associated with on-target side effects for two reasons. The first reason is due to the high sequence conservation at the orthosteric ACh binding site among all five receptor subtypes (M1-M5), making on-target subtype selectivity a major challenge. The second reason is due to on-target side effects of mAChR drugs that are associated with the pleiotropic nature of mAChR signalling at the level of a single mAChR subtype. Indeed, there is growing evidence that within the myriad of signalling events produced by mAChR ligands, some will have therapeutic benefits, whilst others may promote cholinergic side effects. This paradigm of drug action, known as ligand bias or biased agonism, is an attractive feature for next-generation mAChR drugs, as it holds the promise of developing drugs devoid of on-target adverse effects. Although relatively simple to detect and even quantify in vitro, ligand bias, as observed in recombinant systems, does not always translate to in vivo systems, which remains a major hurdle in GPCR drug discovery, including the mAChR family. Here we report recent studies that have attempted to detect and quantify ligand bias at the mAChR family, and briefly discuss the challenges associated with biased agonist drug development.

This article is part of the Special Issue on “Ligand Bias”.

Abstract Image

Abstract Image

毒蕈碱乙酰胆碱受体家族的配体偏倚:机遇与挑战。
肌卡因乙酰胆碱受体(mAChRs)是由内源性神经递质乙酰胆碱(ACh)激活的 G 蛋白偶联受体(GPCRs)。mAChR 信号的中断与多种神经系统疾病和非神经系统疾病有关。因此,开发 mAChR 的激动剂和拮抗剂一直是药物发现的主要途径。遗憾的是,由于两个原因,mAChR 配体往往会产生靶向副作用。第一个原因是由于所有五种受体亚型(M1-M5)的正交 ACh 结合位点具有高度的序列保守性,这使得靶亚型选择性成为一大挑战。第二个原因是 mAChR 药物的靶向副作用,这与 mAChR 信号在单一 mAChR 亚型水平上的多效应性质有关。事实上,越来越多的证据表明,在 mAChR 配体产生的无数信号事件中,有些会产生治疗效果,而另一些则会产生胆碱能副作用。这种药物作用模式被称为配体偏向或偏向激动,是下一代 mAChR 药物的一个诱人特征,因为它有望开发出没有靶向不良反应的药物。虽然在体外检测甚至量化配体偏倚相对简单,但在重组系统中观察到的配体偏倚并不总能转化为体内系统,这仍然是包括 mAChR 家族在内的 GPCR 药物发现的主要障碍。在此,我们报告了近期尝试检测和量化 mAChR 家族配体偏倚的研究,并简要讨论了与偏倚激动剂药物开发相关的挑战。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Neuropharmacology
Neuropharmacology 医学-神经科学
CiteScore
10.00
自引率
4.30%
发文量
288
审稿时长
45 days
期刊介绍: Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).
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