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: 8071545
• 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
• 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/8071545
• 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; Health; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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 and in animal models predictive of antipsychotic-like activity. However, the relative contribution of the M1 and M4 mAChRs to the clinical effects of xanomeline or its effects in associated animal models remain unknown. The focus of this application will be to test the hypothesis that selective potentiation of M4 activity, using a recently developed positive allosteric modulator of the M4 mAChR VU152100 described by our group, 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.

描述（由申请人提供）：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更喜欢激动剂Xanomeans，有效地改善了阳性和阴性症状和阴性障碍，并且在精神分裂症患者中观察到了认知障碍。然而，M1和M4 MACHRS对Xanomeline或其在相关动物模型中其作用的临床作用的相对贡献尚不清楚。最近，我们报告了一种使用高度选择性的阳性变构调节剂（PAM）选择性地激活单个MACHR亚型（尤其是M4 MACHR）的新型方法。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。以VU10010为代表的第一系列M4 PAM诱导了M4 ACH浓度响应曲线的47倍增强，在400 nm范围内具有EC50，并且不会引起其他MACHR子类型的激活。虽然VU10010提供了一个重要的工具，可以证明概念研究M4在分子和细胞水平上的阳性变构调节作用，但该化合物不适合体内研究。现在，我们已经开发了几种新型的VU10010类似物，它们具有系统的活跃，并且更容易越过血脑屏障。这些化合物由VU152​​100代表，为研究MACHR激动剂（例如Xanomeline）的神经化学和行为影响提供了前所未有的机会，认为对抗精神病毒活性和认知的增强至关重要。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。 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 MPFC中的突触对于知识治疗剂的抗精神病药有效性很重要。公共卫生相关性：毒蕈碱乙酰胆碱受体（MACHR）激动剂，例如M1/M4偏爱激动剂Xanomeline，有效地改善了精神分裂症和动物模型中的动物模型中观察到的阳性和阴性障碍，并且在患有抗精神病药模型的个体中观察到了认知障碍。但是，M1和M4 MACHRS对Xanomeline或其在相关动物模型中其影响的临床作用的相对贡献尚不清楚。该应用的重点将是测试以下假设：我们小组描述的M4 MACHR VU152​​100的最近开发的积极的变构调节剂将在动物模型中具有可预测与Xanomeline和测试的效果相比的效果的动物模型中具有活性的活性，以测试M4的假设，M4，M4的活性增加了M4，M4，M4，M4，M4，M4，M4，M4 MPFC中谷氨酸能突触的传播被认为对知识治疗剂的抗精神病药有效性很重要。