Muscarinic receptor activators as novel antipsychotic agents

描述（由申请人提供）：最近的临床研究表明，激活毒蕈碱乙酰胆碱受体（machr）的药物在减轻精神分裂症、阿尔茨海默病和其他神经退行性疾病患者的精神病症状方面具有强大的疗效。有证据表明胆碱能药物的抗精神病作用可能是由M1 mAChR亚型介导的。然而，先前开发的选择性激活M1受体的化合物缺乏对M1的真正特异性。这导致了患者由于M2和M3激活而产生的不良反应问题，并且使得无法明确确定这些化合物的行为和临床效果是由M1还是其他mAChR亚型介导的。尽管多个工业和学术实验室做出了重大努力，但仍不可能开发出临床有用的高选择性M1激动剂，这种激动剂作用于正位乙酰胆碱（ACh）结合位点。这可能是由于mAChR亚型之间ACh位点的高度保守性。近年来，我们已经非常成功地建立了一类新的化合物，作为G蛋白偶联受体的变构增强剂，可能为直接作用激动剂提供关键优势。与激动剂不同，这些化合物不直接激活受体，而是在变构部位起作用，以增强对内源性激动剂的反应。一般来说，这些化合物对预期受体的选择性更强，因为它们不与高度保守的神经递质结合位点相互作用。另一个重大突破是，其他实验室发现了一类新的M1激动剂，它们与受体上的异位位点而不是ACh结合位点相互作用。与传统激动剂不同，这些化合物相对于其他mAChR亚型对M1具有高度特异性，并提供了令人兴奋的新工具，以明确确定被认为对抗精神病活性重要的mAChR激动剂的生理和行为作用是否由M1介导。在拟议的研究中，我们将利用自动化技术和我们开发的M1变构增效剂的高通量筛选来鉴定作为该受体高选择性变构增效剂的新化合物。此外，我们将使用这些化合物与新的选择性异位M1激动剂、一种新的M4变构增强剂和一组特定的mAChR亚型被删除的小鼠一起，来检验毒蕈碱激动剂的抗精神病样特征是由M1介导的这一假设，并确定M1的变构增强剂是否具有与M1激动剂相似的电生理和行为作用。

DESCRIPTION (provided by applicant): Recent clinical studies reveal that agents that activate muscarinic acetylcholine receptors (mAChRs) have robust efficacy in reducing psychotic symptoms in patients with schizophrenia as well as AD and other neurodegenerative disorders. Evidence suggests that the antipsychotic effects of cholinergic agents may be mediated by the M1 mAChR subtype. However, previous compounds developed to selectively activate M1 receptors lack true specificity for M1. This has resulted in problems with adverse effects due to M2 and M3 activation in patients and has made it impossible to definitively determine whether the behavioral and clinical effects of these compounds are mediated by M1 or other mAChR subtypes. Despite major efforts by multiple industry and academic laboratories, it has been impossible to develop clinically useful highly selective M1 agonists that act the orthosteric acetylcholine (ACh) binding site. This is likely due to the high degree of conservation of the ACh site between mAChR subtypes. In recent years we have been highly successful in establishing a new class of compounds that act as allosteric potentiators of G protein-coupled receptors that may provide key advantages to direct-acting agonists. Unlike agonists, these compounds do not directly activate the receptor but act at an allosteric site to potentiate the response to the endogenous agonist. In general, these compounds tend to be more selective for the intended receptor because they do not interact with the highly conserved neurotransmitter binding site. Another major breakthrough occurred when other laboratories discovered a novel class of M1 agonists that interact with an ectopic site on the receptor rather than the ACh binding site. Unlike traditional agonists, these compounds are highly specific for M1 relative to other mAChR subtypes and provide exciting new tools to definitively determine whether the physiological and behavioral effects of mAChR agonists thought to be important for antipsychotic activity are mediated by M1. In the proposed studies, we will take advantage of automated technologies and a high throughput screen for allosteric potentiators of M1 that we have developed to identify novel compounds that act as highly selective allosteric potentiators of this receptor. In addition, we will use these compounds along with the new selective ectopic site M1 agonists, a novel M4 allosteric potentiator and a panel of mice in which specific mAChR subtypes have been deleted to test the hypothesis that the antipsychotic-like profile of muscarinic agonists is mediated by M1 and to determine whether allosteric potentiators of M1 have electrophysiological and behavioral effects that are similar to those of M1 agonists.