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: 7922737
• 负责人: Carrie Kimberly Jones
• 金额: $ 38.98万
• 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/7922737
• 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; Hallucinogens; Impaired cognition; Individual; Knockout Mice; Medial; Mediating; Memory; 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; public health relevance; 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 优先激动剂 xanomeline，可有效改善患有以下疾病的个体中观察到的阳性和阴性症状以及认知障碍：精神分裂症。然而，M1 和 M4 mAChR 对 xanomeline 临床效果或其在相关动物模型中的影响的相对贡献仍然未知。最近，我们报道了一种使用高选择性正变构调节剂（PAM）选择性激活单个 mAChR 亚型（特别是 M4 mAChR）的新方法的开发。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）可诱导 M4 ACh 浓度响应曲线增强 47 倍，EC50 在 400 nM 范围内，并且不会激活其他 mAChR 亚型。虽然 VU10010 为 M4 在分子和细胞水平上的正变构调节作用的概念验证研究提供了重要工具，但该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，它们具有全身活性并且更容易穿过血脑屏障。这些以 VU152​​100 为代表的化合物为研究 mAChR 激动剂（例如 xanomeline）的神经化学和行为效应是否由 M4 介导提供了前所未有的机会，这些激动剂被认为对于抗精神病活性和认知增强很重要。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 小鼠来严格测试这样的假设：M4 活性的选择性增强将在动物模型中发挥作用，预测精神分裂症治疗的功效与观察到的效果相当。 xanomeline 并测试 M4 活性增加将调节中脑边缘多巴胺神经传递和 mPFC 谷氨酸突触传递的假设，这被认为是重要的了解已知治疗剂的抗精神病功效。公共健康相关性：毒蕈碱乙酰胆碱受体 (mAChR) 激动剂，例如 M1/M4 优先激动剂 xanomeline，可有效改善精神分裂症患者和预测抗精神病药样活性的动物模型中观察到的阳性和阴性症状以及认知障碍。然而，M1 和 M4 mAChR 对 xanomeline 临床效果或其在相关动物模型中的影响的相对贡献仍然未知。本申请的重点将是测试以下假设：使用我们小组描述的最近开发的 M4 mAChR VU152​​100 的正变构调节剂选择性增强 M4 活性，将在动物模型中具有活性，预测治疗精神分裂症的疗效可比观察用 xanomeline 观察到的效果，并检验 M4 活性增加将调节中脑边缘多巴胺神经传递和谷氨酸能传递的假设mPFC 中的突触被认为对于已知治疗药物的抗精神病功效很重要。