Medicinal Chemistry and Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
ACS Chem Neurosci. 2013 Jul 17;4(7):1026-48. doi: 10.1021/cn400086m. Epub 2013 May 23.
Since the cholinergic hypothesis of memory dysfunction was first reported, extensive research efforts have focused on elucidating the mechanisms by which this intricate system contributes to the regulation of processes such as learning, memory, and higher executive function. Several cholinergic therapeutic targets for the treatment of cognitive deficits, psychotic symptoms, and the underlying pathophysiology of neurodegenerative disorders, such as Alzheimer's disease and schizophrenia, have since emerged. Clinically approved drugs now exist for some of these targets; however, they all may be considered suboptimal therapeutics in that they produce undesirable off-target activity leading to side effects, fail to address the wide variety of symptoms and underlying pathophysiology that characterize these disorders, and/or afford little to no therapeutic effect in subsets of patient populations. A promising target for which there are presently no approved therapies is the M1 muscarinic acetylcholine receptor (M1 mAChR). Despite avid investigation, development of agents that selectively activate this receptor via the orthosteric site has been hampered by the high sequence homology of the binding site between the five muscarinic receptor subtypes and the wide distribution of this receptor family in both the central nervous system (CNS) and the periphery. Hence, a plethora of ligands targeting less structurally conserved allosteric sites of the M1 mAChR have been investigated. This Review aims to explain the rationale behind allosterically targeting the M1 mAChR, comprehensively summarize and critically evaluate the M1 mAChR allosteric ligand literature to date, highlight the challenges inherent in allosteric ligand investigation that are impeding their clinical advancement, and discuss potential methods for resolving these issues.
自从胆碱能假说被首次提出以来，大量的研究工作集中在阐明这个复杂系统如何调节学习、记忆和高级执行功能等过程的机制上。此后，出现了一些针对认知障碍、精神病症状和神经退行性疾病（如阿尔茨海默病和精神分裂症）潜在病理生理学的胆碱能治疗靶点。目前已经有一些针对这些靶点的临床批准药物；然而，它们都可能被认为是不理想的治疗方法，因为它们会产生不良的脱靶活性，导致副作用，无法解决这些疾病的各种症状和潜在病理生理学，并且/或者在患者群体的某些亚群中几乎没有治疗效果。目前还没有批准的治疗方法的一个有前途的靶点是 M1 毒蕈碱乙酰胆碱受体（M1 mAChR）。尽管进行了深入研究，但由于五个毒蕈碱受体亚型之间结合位点的高度序列同源性以及该受体家族在中枢神经系统（CNS）和外周组织中的广泛分布，通过正位点选择性激活该受体的药物的开发受到了阻碍。因此，已经研究了大量针对 M1 mAChR 较少结构保守的变构位点的配体。这篇综述旨在解释变构靶向 M1 mAChR 的基本原理，全面总结和批判性评估迄今为止关于 M1 mAChR 变构配体的文献，突出变构配体研究中固有的挑战，这些挑战阻碍了它们的临床进展，并讨论解决这些问题的潜在方法。
