Cognitive effects of muscarinic M1 functional agonists in non-human primates and clinical trials.
Cognitive effects of muscarinic M1 functional agonists in non-human primates and clinical trials.
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发表时间：
2010-07
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通讯作者：
R. Mcarthur;J. Gray;R. Schreiber
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作者：
R. Mcarthur;J. Gray;R. Schreiber
AChE抑制剂和NMDA受体拮抗剂用于治疗阿尔茨海默病的认知症状的有限效果促使人们寻找不仅能够治疗行为症状，而且能够改变疾病过程的新药。在过去的十年中，相当多的研究工作集中在正构毒蕈碱M1功能激动剂上，以解决这两种策略。这项研究的一部分包括使用非人灵长类动物作为认知障碍模型，以证明临床前疗效。没有M1功能激动剂已成功注册用于治疗阿尔茨海默病，主要是因为机制相关的不良副作用和边际认知效应。然而，M1激动剂xanomeline表现出治疗精神分裂症阴性和认知症状的临床前和临床疗效。这些结果促使人们重新关注重新定位化合物，如用于该适应症的沙可美林（Proximagen Group plc），以及开发变构毒蕈碱M1配体以提高疗效，同时减少副作用相关的磨损。这篇综述讨论了正构M1功能激动剂的临床前和临床数据，重点是灵长类动物认知研究中的靶点验证，并为测试新一代M1配体和具有新作用机制的化合物提供了建议。
The limited effect of AChE inhibitors and NMDA receptor antagonists for the treatment of the cognitive symptoms of Alzheimer's disease has prompted the search for new drugs that are capable not only of treating behavioral symptoms, but also of modifying the disease process. Considerable research efforts have been focused on orthosteric muscarinic M1 functional agonists during the past decade to address both these strategies. Part of this research has included the use of non-human primates as models of cognitive impairment to demonstrate preclinical efficacy. No M1 functional agonist has been successfully registered for the treatment of Alzheimer's disease, mostly because of mechanism-related adverse side effects and marginal cognitive effects. However, the M1 agonist xanomeline exhibited preclinical and clinical efficacy for the treatment of the negative and cognitive symptoms of schizophrenia. These results prompted renewed interest in repositioning compounds such as sabcomeline (Proximagen Group plc) for this indication, as well as developing allosteric muscarinic M1 ligands to improve efficacy while reducing side-effect-related attrition. This review discusses preclinical and clinical data from orthosteric M1 functional agonists, focusing on target validation in primate cognition studies, and provides recommendations for testing a new generation of M1 ligands and compounds with novel mechanisms of action.