M4 Positive Allosteric Modulators for the Treatment of Schizophrenia

M4 正变构调节剂治疗精神分裂症

基本信息

批准号：
8269701
负责人：
Carrie Kimberly Jones
金额：
$ 38.61万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-28 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8269701
关键词：
Acetylcholine Address Agonist Alzheimer&apos s Disease Animal Model Antipsychotic Agents Autopsy Behavioral Behavioral Symptoms Binding Sites Blood - brain barrier anatomy Cells Chemosensitization Clinical Data Clozapine Cognition Cognitive Corpus striatum structure Development Dopamine Dorsal Glutamates HTR2A gene Hallucinogens Impaired cognition Individual Knockout Mice Medial Mediating Memory Mental disorders Metabotropic Glutamate Receptors Microdialysis Modeling Molecular Muscarinic Acetylcholine Receptor Muscarinics Neuraxis Nucleus Accumbens Patch-Clamp Techniques Patients Phase Prefrontal Cortex Rattus Relative (related person)Reporting Research Rodent Model Role Schizophrenia Series Symptoms Synapses Testing Therapeutic Agents acetylcholine receptor agonist analog atypical antipsychotic brain tissue clinical effect extracellular flexibility human CHRM4 protein improved in vivo nervous system disorder neurochemistry neurotransmission novel novel strategies pre-clinical receptor response tool transmission process xanomeline

项目摘要

PROJECT SUMMARY Preclinical and Phase II clinical data have shown that muscarinic acetylcholine receptor (mAChR) agonists, such as the M1/M4 preferring agonist xanomeline, are effective in improving both positive and negative symptoms and cognitive impairments observed in individuals with schizophrenia. However, the relative contributions of M1 and M4 mAChRs to the clinical effects of xanomeline or its effects in associated animal models remain unknown. Recently, we reported the development of a novel approach to selectively activating individual mAChR subtypes, particularly the M4 mAChR, using highly selective positive allosteric modulators (PAMs). These compounds do not activate M4 directly, but dramatically potentiate the response of the receptor to ACh. The first series of M4 PAMs, represented by VU10010, induces a 47-fold potentiation of the M4 ACh concentration response curve, possesses an EC50 in the 400 nM range, and causes no activation of the other mAChR subtypes. While VU10010 provides an important tool for proof of concept studies on the role of positive allosteric modulation of M4 at molecular and cellular levels, this compound is not suitable for in vivo studies. We have now developed several novel analogs of VU10010 that are systemically active and more readily cross the blood brain barrier. These compounds, represented by VU152100, provide an unprecedented opportunity to investigate whether the neurochemical and behavioral effects of mAChR agonists, such as xanomeline, thought to be important for antipsychotic activity and enhancement of cognition are mediated by M4. Our preliminary studies suggest that VU152100 has robust efficacy in at least one animal model used to predict antipsychotic efficacy. In the proposed studies, we will take advantage of these novel M4 PAMs along with mAChR KO mice to rigorously test the hypothesis that selective potentiation of M4 activity will have activity in animal models that predict efficacy in the treatment of schizophrenia comparable to the effects observed with xanomeline and to test the hypothesis that increased activity of M4 will regulate mesolimbic dopamine neurotransmission and transmission at glutamatergic synapses in the mPFC that are thought to be important for antipsychotic efficacy of know therapeutic agents.

项目概要临床前和 II 期临床数据表明，毒蕈碱乙酰胆碱受体 (mAChR) 激动剂，例如 M1/M4 优先激动剂 xanomeline，可有效改善阳性和阴性在精神分裂症患者中观察到的症状和认知障碍。然而，相对的 M1 和 M4 mAChR 对 xanomeline 的临床效果或其对相关动物的影响的贡献型号仍未知。最近，我们报道了一种新方法的开发，选择性地使用高度选择性的正变构激活单个 mAChR 亚型，特别是 M4 mAChR 调制器 (PAM)。这些化合物不会直接激活 M4，但会显着增强受体对 ACh 的反应。第一个系列的 M4 PAM，以 VU10010 为代表，诱导了 47 倍的 M4 ACh 浓度响应曲线的增强，EC50 在 400 nM 范围内，并且不会引起其他 mAChR 亚型的激活。虽然VU10010提供了一个重要的证明工具关于 M4 在分子和细胞水平上的正变构调节作用的概念研究，这化合物不适合体内研究。我们现已开发出几种新型 VU10010 类似物具有全身活性并且更容易穿过血脑屏障。这些化合物代表通过 VU152100，提供了一个前所未有的机会来研究神经化学和 mAChR 激动剂（例如 xanomeline）的行为影响被认为对于抗精神病药物很重要认知的活动和增强是由 M4 介导的。我们的初步研究表明 VU152100 在至少一种用于预测抗精神病药疗效的动物模型中具有强大的功效。在拟议的研究中，我们将利用这些新型 M4 PAM 和 mAChR KO 小鼠来严格检验 M4 活性的选择性增强在动物模型中具有活性的假设预测精神分裂症治疗效果与 xanomeline 观察到的效果相当并检验 M4 活性增加会调节中脑边缘多巴胺的假设神经传递和 mPFC 中谷氨酸突触的传递被认为是对于已知治疗药物的抗精神病功效很重要。