Ectopic activators of M1 as novel antipsychotic agents

描述(申请人提供)：最近的研究表明，激活M1乙酰胆碱受体(MAChR)的药物可能在临床上有效地治疗精神分裂症和阿尔茨海默病等疾病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通过M1 mAChR亚型介导的，但以前开发的选择性激活M1受体的化合物由于缺乏M1的真正特异性以及与激活其他mAChR亚型相关的不良反应而在临床开发中失败。此外，由于缺乏高度选择性的化合物，因此不可能最终证实这些化合物的行为和临床效应是否由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)高度保守的结合部位所致。避免这个问题的一种可能的方法是鉴定新的激动剂，这些激动剂通过与正构体结合位点在拓扑上不同的异位位点来靶向受体。最近发现的两种新型M1异位激动剂是一项重大突破，它们相对于其他mAChR亚型对M1具有高度特异性。这两种结构上不同的化合物，Acadia PharmPharmticals的AC260584和Conn博士的研究小组发现并鉴定的TBPB，提供了令人兴奋的新工具来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，我将首先建立一种方法来测量M1介导的大鼠海马区细胞外调节激酶(ERK)的激活，以确定系统释放的M1异位激动剂是否可以在体内激活M1。这个测试为我们提供了一个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在三种预测抗精神病活性的经典动物行为模型上的效果，即逆转兴奋剂诱导的过度运动活动，抑制刺激剂诱导的脉冲前抑制的中断，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的正畸激动剂的体内效应，更重要的是，严格测试M1激活在预测人类抗精神病药物疗效的动物模型中的作用这一假设。最终，对这些受体的更好理解可能会导致对患有包括阿尔茨海默病和精神分裂症在内的各种神经退行性疾病患者的治疗方法的改进。

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.