Abstract：
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 D2 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 M1/M4-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.
摘要：
为精神分裂症患者实现最佳治疗结果仍然具有挑战性，尽管有70年的药物开发努力。在过去的七十年中，已经开发了许多化学上不同的抗精神病药，具有改善的安全性和耐受性，但功效仅略有变化。所有目前处方的抗精神病药均作为多巴胺D2受体的拮抗剂或部分激动剂。只有少数可能的例外，抗精神病药物在治疗阳性症状方面具有相似和适度的疗效，并且在解决疾病的阴性和认知症状方面相对无效。专注于靶向毒蕈碱乙酰胆碱受体（mAChRs）的新型治疗方法的开发已经引起了人们的兴趣超过25年，因为有报道称，用优选mAChR激动剂的双M1/M4治疗会导致抗精神病药样作用和认知特性患有阿尔茨海默氏病和精神分裂症的人；最近的临床试验证实了这些发现。此外,我们对黄霉素在特定mAChRs上的受体结合和激活特性的理解的进展有可能为未来靶向mAChRs的药物设计提供信息。
