Muscarinic receptor activators as novel antipsychotic agents

毒蕈碱受体激活剂作为新型抗精神病药

• 批准号: 7163800
• 负责人: P Jeffrey Conn
• 金额: $ 31.62万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/7163800
• 关键词: 4-n-butyl-1-(4-(2-methylphenyl)-4-oxo-1-butyl)-piperidine hydrogen chloride; Acetylcholine; Adverse effects; Agonist; Allosteric Site; Antipsychotic Agents; Behavioral; Binding Sites; Biological Assay; Cells; Chemicals; Cholinergic Agents; Class; Clinical; Clinical Research; Cognitive; Development; FOS gene; G-Protein-Coupled Receptors; Hippocampus (Brain); Industry; Knockout Mice; Laboratories; Libraries; Measures; Mediating; Modeling; Mus; Muscarinic Acetylcholine Receptor; Muscarinic Agonists; Muscarinic M1 Receptor; Neurodegenerative Disorders; Neurotransmitters; Nucleus Accumbens; Patients; Pharmaceutical Preparations; Physiological; Prefrontal Cortex; Process; Property; Prosencephalon; Psychotic Disorders; Receptor Activation; Receptor Signaling; Relative (related person); Research Personnel; Role; Schizophrenia; Site; Specificity; Structure; Symptoms; Technology; Testing; Thinking; Wild Type Mouse; atypical antipsychotic; cholinergic; clinical effect; cognitive function; high throughput screening; immunoreactivity; improved; novel; novel strategies; patch clamp; programs; receptor; response; small molecule; small molecule libraries; tool; transmission process; xanomeline

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功效。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，之前开发的用于选择性激活 M1 受体的化合物缺乏对 M1 的真正特异性。这导致了由于患者中 M2 和 M3 激活而产生不良反应的问题，并且无法明确确定这些化合物的行为和临床效应是否是由 M1 或其他 mAChR 亚型介导的。尽管多个行业和学术实验室付出了巨大努力，但仍不可能开发出临床上有用的、作用于正构乙酰胆碱 (ACh) 结合位点的高选择性 M1 激动剂。这可能是由于 mAChR 亚型之间的 ACh 位点高度保守。近年来，我们在建立一类新化合物方面取得了巨大成功，这些化合物充当 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，而是作用于变构位点以增强对内源激动剂的反应。一般来说，这些化合物往往对预期受体更具选择性，因为它们不与高度保守的神经递质结合位点相互作用。当其他实验室发现一类新型 M1 激动剂时，另一个重大突破发生了，它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，相对于其他 mAChR 亚型，这些化合物对 M1 具有高度特异性，并提供令人兴奋的新工具来明确确定对抗精神病活性重要的 mAChR 激动剂的生理和行为效应是否由 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 变构增强剂的高通量筛选来鉴定充当该受体的高选择性变构增强剂的新型化合物。此外，我们将使用这些化合物以及新的选择性异位点 M1 激动剂、一种新型 M4 变构增效剂和一组已删除特定 mAChR 亚型的小鼠，以测试毒蕈碱激动剂的抗精神病样作用是由 M1 介导的假设，并确定 M1 的变构增效剂是否具有与那些类似的电生理和行为效应。 M1激动剂。