Yohn Samantha E, Harvey Phillip D, Brannan Stephen K, Horan William P
Bristol Myers Squibb, Princeton, NJ, United States.
Division of Psychology, University of Miami, Miami, FL, United States.
Front Psychiatry. 2024 Oct 4;15:1421554. doi: 10.3389/fpsyt.2024.1421554. eCollection 2024.
Cognitive impairment is a core symptom of schizophrenia and a major determinant of poor long-term functional outcomes. Despite considerable efforts, we do not yet have any approved pharmacological treatments for cognitive impairment associated with schizophrenia (CIAS). A combination of advances in pre-clinical research and recent clinical trial findings have led to a resurgence of interest in the cognition-enhancing potential of novel muscarinic acetylcholine receptor (mAChR) agonists in schizophrenia. This article provides an overview of the scientific rationale for targeting M and M mAChRs. We describe the evolution of neuroscience research on these receptors since early drug discovery efforts focused on the mAChR agonist xanomeline. This work has revealed that M and M mAChRs are highly expressed in brain regions that are implicated in cognition. The functional significance of M and M mAChRs has been extensively characterized in animal models via use of selective receptor subtype compounds through neuronal and non-neuronal mechanisms. Recent clinical trials of a dual M/M mAChR agonist show promising, replicable evidence of potential pro-cognitive effects in schizophrenia, with several other mAChR agonists in clinical development.
认知障碍是精神分裂症的核心症状，也是长期功能预后不良的主要决定因素。尽管付出了巨大努力，但对于与精神分裂症相关的认知障碍（CIAS），我们目前仍没有任何获批的药物治疗方法。临床前研究的进展与近期临床试验结果相结合，使得人们对新型毒蕈碱型乙酰胆碱受体（mAChR）激动剂改善精神分裂症认知功能的潜力重新燃起兴趣。本文概述了靶向M和M mAChR的科学原理。我们描述了自早期药物研发工作聚焦于mAChR激动剂占诺美林以来，针对这些受体的神经科学研究的发展历程。这项工作表明，M和M mAChR在与认知相关的脑区中高度表达。通过使用选择性受体亚型化合物，经神经元和非神经元机制，M和M mAChR的功能意义在动物模型中得到了广泛表征。一种双重M/M mAChR激动剂的近期临床试验显示，在精神分裂症中具有潜在促认知作用的证据很有前景且可重复，还有其他几种mAChR激动剂正处于临床开发阶段。
