Schizophrenia remains a challenging disease to treat effectively with current antipsychotic medications due to their limited efficacy across the entire spectrum of core symptoms as well as their often burdensome side-effect profiles and poor tolerability. An unmet need remains for novel, mechanistically unique, and better tolerated therapeutic agents for treating schizophrenia, especially those that treat not only positive symptoms but also the negative and cognitive symptoms of the disease. Almost 25 years ago, the muscarinic acetylcholine receptor (mAChR) agonist xanomeline was reported to reduce psychotic symptoms and improve cognition in patients with Alzheimer’s disease. The antipsychotic and procognitive properties of xanomeline were subsequently confirmed in a small study of acutely psychotic patients with chronic schizophrenia. These unexpected clinical findings have prompted considerable efforts across academia and industry to target mAChRs as a new approach to potentially treat schizophrenia and other psychotic disorders. The authors discuss recent advances in mAChR biology and pharmacology and the current understanding of the relative roles of the various mAChR subtypes, their downstream cellular effectors, and key neural circuits mediating the reduction in the core symptoms of schizophrenia in patients treated with xanomeline. They also provide an update on the status of novel mAChR agonists currently in development for potential treatment of schizophrenia and other neuropsychiatric disorders.

精神分裂症仍然是一种难以用当前的抗精神病药物有效治疗的疾病，因为它们在整个核心症状谱中的疗效有限，而且它们通常具有繁重的副作用和较差的耐受性。对用于治疗精神分裂症的新型、机制独特且耐受性更好的治疗剂，尤其是那些不仅治疗阳性症状而且治疗疾病的阴性和认知症状的治疗剂，仍然存在未满足的需求。大约 25 年前，据报道毒蕈碱乙酰胆碱受体 (mAChR) 激动剂 xanomeline 可减轻阿尔茨海默病患者的精神病症状并改善认知能力。随后在一项针对患有慢性精神分裂症的急性精神病患者的小型研究中证实了 xanomeline 的抗精神病和促认知特性。这些出人意料的临床发现促使学术界和工业界做出了相当大的努力，将 mAChR 作为潜在治疗精神分裂症和其他精神病的新方法。作者讨论了 mAChR 生物学和药理学的最新进展，以及目前对各种 mAChR 亚型的相关作用、它们的下游细胞效应物以及介导使用 xanomeline 治疗的患者精神分裂症核心症状减轻的关键神经回路的理解。他们还提供了目前正在开发用于治疗精神分裂症和其他神经精神疾病的新型 mAChR 激动剂的最新情况。