Ectopic activators of M1 as novel antipsychotic agents

M1 异位激活剂作为新型抗精神病药物

• 批准号: 7626881
• 负责人: ASHLEY BRADY
• 金额: $ 5.48万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7626881
• 关键词: 4-n-butyl-1-(4-(2-methylphenyl)-4-oxo-1-butyl)-piperidine hydrogen chloride; Acetylcholine; Address; Adverse effects; Agonist; Alzheimer' s Disease; Amphetamines; Animal Model; Animals; Antipsychotic Agents; Apomorphine; Behavioral; Behavioral Model; Binding; Binding Sites; Biological Assay; Biological Markers; Chemicals; Chimera organism; Cholinergic Agents; Class; Clinical; Clinical Research; Condition; Development; Disease; Disruption; Dose; Fellowship; Hippocampus (Brain); Human; Individual; Knockout Mice; Lead; Libraries; Measures; Mediating; Mental disorders; Modeling; Molecular; Muscarinic Acetylcholine Receptor; Muscarinic Agonists; Muscarinic M1 Receptor; Mutate; Names; Nerve Degeneration; Neurodegenerative Disorders; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phosphotransferases; Physiologic pulse; Physiological; Point Mutation; Property; Psychotic Disorders; Pulse taking; Range; Rattus; Relative (related person); Research; Schizophrenia; Site; Specificity; Symptoms; Testing; Thinking; Time; acetylcholine receptor agonist; cholinergic; clinical effect; cognitive function; extracellular; high throughput screening; human CHRM1 protein; improved; in vivo; neurotransmission; novel; receptor; scaffold; small molecule; tool; transmission process; xanomeline

DESCRIPTION (provided by applicant): Recent studies suggest that agents that activate the M1 muscarinic acetylcholine receptor (mAChR) may be clinically efficacious in treating psychosis and behavioral disturbances in patients suffering from disorders such as schizophrenia and Alzheimer's disease. While evidence suggests that the antipsychotic effects of cholinergic agents may be mediated by the M1 mAChR subtype, previous compounds developed to selectively activate M1 receptors have failed in clinical development due to a lack of true specificity for M1 and adverse effects associated with activation of other mAChR subtypes. Furthermore, the lack of highly selective compounds has made it impossible to conclusively verify whether the behavioral and clinical effects of these compounds are mediated by M1. The difficulty in developing mAChR subtype-selective compounds is likely due to the highly conserved binding site for acetylcholine (ACh). One potential way to circumvent this problem is to identify novel agonists that target the receptor through ectopic sites that are topographically distinct from that of the orthosteric binding site. A major breakthrough occurred with the recent discovery of two novel M1 ectopic agonists that are highly specific for M1 relative to other mAChR subtypes. These two structurally distinct compounds, AC260584 from Acadia Pharmaceuticals and TBPB, which was discovered and characterized by Dr. Conn's research group, 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 Ml For my studies, I will first develop an assay to measure M1-mediated activation of extracellular regulated kinase (ERK) in rat hippocampus to determine if systemically delivered M1 ectopic site agonists can activate M1 in vivo. This assay provides us with a valuable biomarker for determining appropriate dose ranges and time points necessary for evaluating these compounds in subsequent animal behavioral studies. I will assess the effect of these compounds on three classic animal behavioral models predictive of antipsychotic activity, namely reversal of stimulant-induced hyperlocomotor activity, inhibition of stimulant-induced disruption of pre-pulse inhibition, and inhibition of conditioned avoidance responding. The proposed studies will allow us to ascertain whether M1 ectopic agonists will mimic the in vivo effects of traditional orthosteric agonists and, more importantly, to rigorously test the hypothesis that activation of M1 has effects in animal models predictive of antipsychotic efficacy in humans. Ultimately, a better understanding of these receptors may lead to improved therapies for patients suffering from a variety of neurodegenerative disorders including Alzheimer's disease and Schizophrenia.

描述（由申请人提供）：最近的研究表明，激活M1毒蕈碱乙酰胆碱受体（mAChR）的药物在治疗患有精神分裂症和阿尔茨海默病等疾病的患者的精神病和行为障碍方面可能具有临床有效性。虽然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，但由于缺乏对M1的真正特异性以及与其他mAChR亚型激活相关的不良反应，先前开发的选择性激活M1受体的化合物在临床开发中失败。此外，由于缺乏高选择性化合物，因此无法最终验证这些化合物的行为和临床作用是否由M1介导。开发mAChR亚型选择性化合物的困难可能是由于乙酰胆碱（ACh）的高度保守的结合位点。一个潜在的方法来规避这个问题是确定新的激动剂，通过异位的网站是地形不同的正构结合位点的受体为目标。最近发现了两种新型M1异位激动剂，取得了重大突破，相对于其他mAChR亚型，它们对M1具有高度特异性。这两种结构上不同的化合物，即来自Escheridia Pharmaceuticals的AC260584和由Conn博士的研究小组发现和表征的TBPB，提供了令人兴奋的新工具来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MI介导。我将首先开发一种测定方法来测量M1介导的激活细胞外调节激酶（ERK）在大鼠海马，以确定是否全身提供M1异位部位激动剂可以激活M1在体内。该测定为我们提供了一种有价值的生物标志物，用于确定在随后的动物行为研究中评价这些化合物所需的适当剂量范围和时间点。我将评估这些化合物对三种经典的动物行为模型的影响，这些模型预测抗精神病活性，即逆转兴奋剂诱导的hypermotormotion活动，抑制兴奋剂诱导的前脉冲抑制中断，抑制条件回避反应。拟议的研究将使我们能够确定M1异位激动剂是否会模仿传统的正构激动剂的体内作用，更重要的是，严格检验M1的激活在动物模型中具有预测人类抗精神病疗效的作用的假设。最终，更好地了解这些受体可能会导致改善治疗患有各种神经退行性疾病，包括阿尔茨海默病和精神分裂症的患者。