Muscarinic receptor activators as antipsychotic agents

作为抗精神病药物的毒蕈碱受体激活剂

基本信息

批准号：
7034693
负责人：
P Jeffrey Conn
金额：
$ 32.41万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-01 至 2010-12-31
项目状态：
已结题

项目摘要

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.

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）的药物在减少精神分裂症患者以及AD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效率。有证据表明，胆碱能剂的抗精神病药作用可以由M1 MACHR亚型介导。然而，以前开发的化合物有选择地激活M1受体缺乏对M1的真正特异性。这导致由于患者的M2和M3激活引起的不良影响问题，因此无法确定确定这些化合物的行为和临床作用是否由M1或其他MACHR亚型介导。尽管多个行业和学术实验室做出了巨大的努力，但不可能开发出临床上有用的高度选择性的M1激动剂，这些激动剂将其作用于正构乙酰胆碱（ACH）结合位点。这可能是由于MACHR亚型之间的ACH位点的高度保护。近年来，我们在建立一类新的化合物方面非常成功，这些化合物是G蛋白偶联受体的变构增强剂，这些受体可能为直接作用激动剂提供关键的优势。与激动剂不同，这些化合物不会直接激活受体，而是在变构部位作用以增强对内源性激动剂的反应。通常，这些化合物对预期的受体往往更具选择性，因为它们与高度保守的神经递质结合位点不相互作用。当其他实验室发现一种新型的M1激动剂时，与受体上的异位部位相互作用而不是ACH结合位点时，发生了另一个重大突破。与传统激动剂不同，这些化合物相对于其他MACHR亚型高度特异性，并提供了令人兴奋的新工具，可以确定地确定MACHR激动剂的生理和行为影响是否被认为对抗精神病毒活性很重要。在拟议的研究中，我们将利用自动化技术和M1的变构增强剂的高吞吐量屏幕，以鉴定新型化合物，这些化合物是该受体的高度选择性的变构增强剂。此外，我们将使用这些化合物以及新的选择性异位部位M1激动剂，一种新型的M4变构增强剂和一组小鼠，其中已删除了特定的MACHR亚型，以测试以下假说，即肌肉促是肌肉毒但是类动物的抗精神病药物概况是由M1介导，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效应。