Selective M1 mAChR allosteric modulators for the treatment of schizophrenia

描述（由申请人提供）：50多年前，抗uscarinic药物被证明在人类中诱导类似于精神分裂症的精神状态，并加剧精神分裂症患者现有的症状。大约在这个时候，毒蕈碱激动剂被证明是中度有效的神经镇静剂，这就产生了精神分裂症的胆碱能假说，比现在流行的高多巴胺能假说早了几十年。最近的临床前和III期临床数据进一步加强了胆碱能假说，表明毒蕈碱类乙酰胆碱受体（mAChR）激动剂，如泛毒蕈碱类激动剂xanomeline，可有效改善精神分裂症和阿尔茨海默病（AD）患者的认知和减轻精神病症状。然而，由于缺乏mAChR亚型选择性导致无法忍受的副作用，mAChR激动剂的临床应用受到限制。在毒蕈碱受体的五种亚型（M1-M5）中，乙酰胆碱（ACh）的正位结合位点高度保守，因此亚型选择性毒蕈碱激动剂的开发一直很困难。我们已经确定并计划开发新的，选择性的M1 mAChR的变构激动剂和增强剂，通过变构结合位点激活受体，该位点在拓扑结构上与正构结合位点不同。由于越来越多的证据表明，胆碱能药物的认知、抗精神病和降低Ab的作用是由M1 mAChR亚型介导的，因此我们进行了高通量筛选，以鉴定M1增强剂和变构激动剂。这一努力提供了代表多种新化学型的小分子M1增强剂和M1变构激动剂先导物。虽然这是一项重大成就，但这些筛选先导物将需要几轮化学先导物优化，以生产M1变构激动剂和M1增强剂，适合作为概念验证工具进行体内研究。此外，我们在TBPB的评估方面取得了重大进展，TBPB是一种高选择性和强效的体内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。我们这个项目的目标是同时开发选择性M1变构激动剂和M1阳性变构调节剂，它们具有可接受的临床前和最终临床开发特征，可能导致一种用于治疗精神分裂症阳性、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期临床数据显示，毒蕈碱类乙酰胆碱受体（mAChR）激动剂，如泛毒蕈碱类激动剂xanomeline，在改善精神分裂症和阿尔茨海默病（AD）患者的认知和减轻精神病症状方面有效。我们已经完成了高通量筛选，确定并计划开发新的、选择性的M1 mAChR变构激动剂和增强剂，通过一个新的结合位点激活受体，为M1与M2-M5提供完全的、前所未有的选择性。我们这个项目的目标是同时开发选择性M1变构激动剂和M1阳性变构调节剂，它们具有可接受的临床前和最终临床开发特征，可能导致一种用于治疗精神分裂症阳性、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.