Ectopic activators of M1 as novel antipsychotic agents

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）的药物可能在临床上有效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。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，但之前开发的用于选择性激活 M1 受体的化合物在临床开发中失败了，因为缺乏对 M1 的真正特异性以及与其他 mAChR 亚型激活相关的不良反应。此外，由于缺乏高度选择性的化合物，因此无法最终验证这些化合物的行为和临床效果是否是由 M1 介导的。开发 mAChR 亚型选择性化合物的困难可能是由于乙酰胆碱 (ACh) 的结合位点高度保守。解决这个问题的一种潜在方法是鉴定通过与正构结合位点在拓扑上不同的异位位点靶向受体的新型激动剂。最近发现了两种新型 M1 异位激动剂，这是一项重大突破，相对于其他 mAChR 亚型，它们对 M1 具有高度特异性。这两种结构不同的化合物，来自 Acadia 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，可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效应是否由 M1 介导。在我的研究中，我将首先开发一种测定法来测量大鼠海马中 M1 介导的细胞外调节激酶 (ERK) 的激活，以确定是否全身递送M1异位激动剂可以在体内激活M1。该测定为我们提供了有价值的生物标志物，用于确定在后续动物行为研究中评估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预测抗精神病活性的三种经典动物行为模型的影响，即逆转兴奋剂诱导的运动过度活性、抑制兴奋剂诱导的前脉冲抑制破坏以及抑制条件性回避反应。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正位激动剂的体内作用，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药功效的作用的假设。最终，更好地了解这些受体可能会改善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）的患者的治疗方法。

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.