Achieving optimal treatment outcomes for individuals living with schizophrenia remains challenging, despite 70 years of drug development efforts. Many chemically distinct antipsychotics have been developed over the past 7 decades with improved safety and tolerability but with only slight variation in efficacy. All antipsychotics currently approved for the treatment of schizophrenia act as antagonists or partial agonists at the dopamine D receptor. With only a few possible exceptions, antipsychotic drugs have similar and modest efficacy for treating positive symptoms and are relatively ineffective in addressing the negative and cognitive symptoms of the disease. The development of novel treatments focused on targeting muscarinic acetylcholine receptors (mAChRs) has been of interest for more than 25 years following reports that treatment with a dual M/M–preferring mAChR agonist resulted in antipsychotic-like effects and procognitive properties in individuals living with Alzheimer’s disease and schizophrenia; more recent clinical trials have confirmed these findings. In addition, advances in our understanding of the receptor binding and activation properties of xanomeline at specific mAChRs have the potential to inform future drug design targeting mAChRs.

中文翻译：

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毒蕈碱受体激活剂作为精神分裂症的新疗法


尽管经过 70 年的药物开发努力，为精神分裂症患者实现最佳治疗结果仍然具有挑战性。过去 7 年来，人们开发出了许多化学性质不同的抗精神病药物，其安全性和耐受性有所提高，但疗效仅略有不同。目前批准用于治疗精神分裂症的所有抗精神病药物均充当多巴胺 D 受体的拮抗剂或部分激动剂。除少数可能的例外情况外，抗精神病药物对于治疗阳性症状具有相似且适度的功效，并且在解决疾病的阴性和认知症状方面相对无效。 25 年来，针对毒蕈碱乙酰胆碱受体 (mAChR) 的新型治疗方法的开发一直受到人们的关注，此前有报道称，使用双 M/M 偏好的 mAChR 激动剂治疗可在患有精神分裂症的个体中产生类似抗精神病药的作用和促认知特性。阿尔茨海默病和精神分裂症；最近的临床试验证实了这些发现。此外，我们对 xanomeline 在特定 mAChR 上的受体结合和激活特性的理解的进展有可能为未来针对 mAChR 的药物设计提供信息。