Selective M1 mAChR allosteric modulators for the treatment of schizophrenia

描述（由申请人提供）：50多年前，抗毒蕈碱剂显示在人类中诱导类似于精神分裂症的精神病状态，并加重精神分裂症患者的现有症状。大约在这个时候，毒蕈碱激动剂被证明是适度有效的神经安定剂，这引起了精神分裂症的胆碱能假说，几十年前，现在流行的高多巴胺能假说。最近的临床前和III期临床数据进一步加强了胆碱能假说，证明毒蕈碱乙酰胆碱受体（mAChR）激动剂，如泛毒蕈碱激动剂xanomeline，有效地改善认知和减少精神分裂症和阿尔茨海默病（AD）患者的精神病症状。然而，由于缺乏mAChR亚型选择性导致的不可耐受的副作用，mAChR激动剂的临床用途受到限制。在M1-M5受体亚型中，乙酰胆碱（ACh）的正构结合位点高度保守，因此，亚型选择性激动剂的开发一直是一个难题。我们已经确定并计划开发新的，选择性的变构激动剂和增效剂的M1 mAChR激活受体通过变构结合位点，这是拓扑结构不同的正构结合位点。由于越来越多的证据表明，认知，抗精神病和抗体降低胆碱能药物的影响是由M1 mAChR亚型介导的，我们已经进行了高通量筛选，以确定M1增效剂和变构激动剂。这一努力提供了代表多种新化学型的小分子M1增效剂和M1变构激动剂先导物。虽然这是一项重大成就，但这些筛选先导化合物将需要几轮化学先导化合物优化，以产生适合作为体内研究概念验证工具的M1变构激动剂和M1增效剂。此外，我们在评价TBPB方面取得了重大进展，TBPB是一种高度选择性和有效的M1变构激动剂，这进一步支持了我们追求选择性M1激活作为精神分裂症治疗的策略。这项研究与NIMH的使命直接相关，并有可能直接影响人类健康。本项目的目标是平行开发选择性M1变构激动剂和M1阳性变构调节剂，其临床前和最终临床开发具有可接受的特征，可能导致用于治疗精神分裂症的阳性，阴性和认知症状的新药。公共卫生相关性：最近的临床前和III期临床数据表明，毒蕈碱乙酰胆碱受体（mAChR）激动剂，如泛毒蕈碱激动剂xanomeline，可有效改善精神分裂症和阿尔茨海默病（AD）患者的认知和减少精神病症状。我们已经完成了高通量筛选，确定并计划开发M1 mAChR的新型选择性变构激动剂和增强剂，其通过新型结合位点激活受体，从而为M1与M2-M5提供完全的前所未有的选择性。本项目的目标是平行开发选择性M1变构激动剂和M1阳性变构调节剂，其临床前和最终临床开发具有可接受的特征，可能导致用于治疗精神分裂症的阳性，阴性和认知症状的新药。

DESCRIPTION (provided by applicant): Over 50 years ago, antimuscarinic agents were shown to induce a psychotic state in humans similar to schizophrenia and exacerbate existing symptoms in schizophrenic patients. At about this time, muscarinic agonists were shown to be moderately effective as neuroleptic agents, which gave rise a cholinergic hypothesis of schizophrenia, decades before the now prevalent hyperdopaminergic hypothesis. Recent preclinical and Phase III clinical data further strengthens the cholinergic hypothesis by demonstrating that muscarinic acetylcholine receptor (mAChR) agonists, such as the pan-muscarinic agonist xanomeline, are effective in improving cognition and reducing psychotic symptoms in schizophrenic and Alzheimer's disease (AD) patients. However, the clinical utility of of mAChR agonists has been limited due to intolerable side effects resulting from a lack of mAChR subtype selectivity. The development of subtype selective muscarinic agonists has been difficult to the highly conserved orthosteric binding site for acetylcholine (ACh) among the five muscarinic receptor subtypes (M1-M5). We have identified and plan to develop novel, selective allosteric agonists and potentiators of the M1 mAChR that activate the receptor through an allosteric binding site that is topologically distinct from the orthosteric binding site. Since mounting evidence suggests that the cognitive, antipsychotic and Ab lowering effects of cholinergic agents are mediated by the M1 mAChR subtype, we have performed a high throughput screen to identify M1 potentiators and allosteric agonists. This effort afforded small molecule M1 potentiators and M1 allosteric agonist leads representing multiple new chemotypes. While a significant accomplishment, these screening leads will require several rounds of chemical lead optimization in order to produce M1 allosteric agonists and M1 potentiators suitable as proof of concept tools to study in vivo. In addition, we have made significant progress in the evaluation of TBPB, a highly selective and potent M1 allosteric agonist in vivo, which further supports our strategy of pursuing selective M1 activation as a treatment for schizophrenia. This research has direct relevance to the mission of NIMH and has the potential to impact human health directly. Our goal for this project is to develop, in parallel, selective M1 allosteric agonists and M1 positive allosteric modulators with acceptable profiles for preclinical and ultimately clinical development that may lead to a new drug for the treatment of the positive, negative and cognitive symptoms of schizophrenia. PUBLIC HEALTH RELEVANCE: Recent preclinical and Phase III clinical data has shown that muscarinic acetylcholine receptor (mAChR) agonists, such as the pan-muscarinic agonist xanomeline, are effective in improving cognition and reducing psychotic symptoms in schizophrenic and Alzheimer's disease (AD) patients. We have completed a high throughput screen, identified and plan to develop novel, selective allosteric agonists and potentiators of the M1 mAChR that activate the receptor through a novel binding site which affords complete, unprecedented selectivity for M1 versus M2-M5. Our goal for this project is to develop, in parallel, selective M1 allosteric agonists and M1 positive allosteric modulators with acceptable profiles for preclinical and ultimately clinical development that may lead to a new drug for the treatment of the positive, negative and cognitive symptoms of schizophrenia.