M4 Positive Allosteric Modulators for the Treatment of Schizophrenia

M4 正变构调节剂治疗精神分裂症

• 批准号: 8468210
• 负责人: Carrie Kimberly Jones
• 金额: $ 37.07万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-28 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8468210
• 关键词: Acetylcholine; Address; Agonist; Alzheimer' 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

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.

项目摘要 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偏爱激动剂Xanomeline，可有效改善正面和阴性 精神分裂症患者观察到的症状和认知障碍。但是，亲戚 M1和M4 MACHR对Xanomeline或其对相关动物的影响的临床作用的贡献 模型仍然未知。最近，我们报告了一种新颖方法的发展 使用高选择性阳性变构激活单个MACHR亚型，尤其是M4 MACHR 调节器（PAMS）。这些化合物不会直接激活M4，而是显着增强 受体对ACH的反应。由VU10010代表的第一个M4 PAM系列诱导47倍 M4 ACH浓度响应曲线的增强，在400 nm范围内具有EC50，并且 不会引起其他MACHR子类型的激活。而VU10010为证明的重要工具提供了 关于M4在分子和细胞水平上的阳性变构调节作用的概念研究，这 化合物不适合体内研究。我们现在已经开发了几种VU10010的新型类似物 具有系统性的活动，并且更容易越过血脑屏障。这些化合物表示 通过VU152​​100，提供了一个前所未有的机会来调查神经化学和是否是否 MACHR激动剂的行为影响，例如Xanomeline，认为对抗精神病药很重要 认知的活性和增强是由M4介导的。我们的初步研究表明 VU152​​100在至少一种用于预测抗精神病毒功效的动物模型中具有强大的功效。在 拟议的研究，我们将利用这些新型M4 PAM以及MACHR KO小鼠到 严格检验以下假设，即M4活性的选择性增强将在动物模型中具有活性 这可以预测与Xanomeline观察到的效果相当的精神分裂症治疗的功效 并检验假设M4的活性增加将调节中唇多巴胺 MPFC中谷氨酸能突触的神经传递和传播被认为是 对于知识治疗剂的抗精神病药疗效很重要。