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Discovery of mGlu receptor PAMs for treatment of schizophrenia

发现 mGlu 受体 PAM 用于治疗精神分裂症

基本信息

批准号：
10531546
负责人：
P Jeffrey Conn
金额：
$ 67.81万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10531546
关键词：
Adverse effects Animal Model Antipsychotic Agents Area Cellular Neurobiology Chemicals Chemistry Clinical Clinical Research Cognitive deficits Corpus striatum structure Coupled Data Development Dopamine Dopamine D1 Receptor Drug Kinetics Endocannabinoids Equilibrium G-Protein-Coupled Receptors GRM1 gene Genes Genetic study Human Human Genetics Investigational Drugs Lead Ligands Light Medicine Metabotropic Glutamate Receptors Modeling Molecular Motivation Muscarinic Acetylcholine Receptor Neurobehavioral Manifestations Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Positioning Attribute Prefrontal Cortex Property Rapid screening Receptor Signaling Rodent Model Schizophrenia Series Signal Transduction Single Nucleotide Polymorphism Symptoms Testing associated symptom clinical development dopaminergic neuron drug candidate drug discovery drug metabolism efficacy evaluation experimental study genome wide association study high throughput screening improved in vivo lead optimization loss of function novel novel strategies novel therapeutics pharmacologic positive allosteric modulator pre-clinical preclinical development preclinical study scaffold screening social deficits treatment strategy

项目摘要

Recent clinical and preclinical, and human genetic studies suggest that selective positive allosteric modulators (PAMs) of the mGlu1 subtype of metabotropic glutamate (mGlu) receptor have exciting potential as a novel approach for treatment of schizophrenia. We found that highly selective mGlu1 PAMs exert their antipsychotic-like effects in animal models by selectively inhibiting dopamine (DA) release in the striatum but not in extrastriatal regions, where inhibition of DA signaling could contribute to adverse effects of existing antipsychotic agents. Furthermore, we present exciting new data showing that mGlu1 PAMs have specific actions within the prefrontal cortex (PFC) that can reverse pathophysiological changes in specific cortical circuits that are disrupted in schizophrenia patients, and can reverse specific cognitive and social deficits in rodent models. Thus, mGlu1 PAMs could provide robust antipsychotic efficacy through actions of DA signaling, and may also improve some negative symptoms and cognitive deficits in schizophrenia patients by reducing pathophysiological changes in specific cortical circuits. It will now be important to optimize highly selective mGlu1 PAMs that are suitable for advancing to clinical development to allow clinical studies to directly assess the utility of these compounds as a novel strategy for treatment of schizophrenia. We recently made a major breakthrough in discovery and optimization of multiple highly selective mGlu1 PAMs that have excellent drug- like properties. These compounds provide exciting new drug leads that can provide the basis of a focused effort to optimize novel mGlu1 PAMs that are suitable for advancing to preclinical and clinical development. We have been highly successful in optimizing multiple selective ligands for other mGlu receptors and other GPCR subtypes as drug candidates that are now advancing in preclinical and clinical development. This places us in an excellent position to optimize selective mGlu1 PAMs as drug candidates for treatment of positive symptoms associated with schizophrenia and to further assess the potential utility of these compounds in reversing specific negative symptoms and cognitive deficits. We now propose a series of studies in which we will optimize highly selective mGlu1 PAMs suitable for preclinical proof of concept studies and that have the properties required so that they can subsequently be advanced IND-enabling studies and clinical development.

最近的临床和临床前以及人类遗传学研究表明，选择性正变构代谢型谷氨酸 (mGlu) 受体 mGlu1 亚型的调节剂 (PAM) 具有令人兴奋的潜力，如一种治疗精神分裂症的新方法。我们发现高度选择性的 mGlu1 PAM 发挥其作用通过选择性抑制纹状体中多巴胺 (DA) 的释放，在动物模型中产生抗精神病样作用，但不在纹状体外区域，抑制 DA 信号传导可能会导致现有的不良影响抗精神病药物。此外，我们提供了令人兴奋的新数据，表明 mGlu1 PAM 具有特定的前额皮质 (PFC) 内的作用可以逆转特定皮质的病理生理变化精神分裂症患者的神经回路被破坏，可以逆转精神分裂症患者的特定认知和社交缺陷啮齿动物模型。因此，mGlu1 PAM 可以通过 DA 信号传导提供强大的抗精神病功效，还可以通过减少精神分裂症患者的一些阴性症状和认知缺陷来改善特定皮质回路的病理生理变化。现在重要的是优化高度选择性 mGlu1 PAM 适合推进临床开发，以便临床研究直接评估这些化合物作为治疗精神分裂症的新策略的用途。我们最近做了一个重大的多种高选择性 mGlu1 PAM 的发现和优化取得突破，这些药物具有优异的药物喜欢属性。这些化合物提供了令人兴奋的新药先导物，可以为重点关注的药物提供基础努力优化适合推进临床前和临床开发的新型 mGlu1 PAM。我们在优化其他 mGlu 受体和其他药物的多种选择性配体方面取得了巨大成功。 GPCR 亚型作为候选药物目前正在临床前和临床开发中取得进展。这使我们处于有利地位，可以优化选择性 mGlu1 PAM 作为治疗以下疾病的候选药物与精神分裂症相关的阳性症状并进一步评估这些化合物的潜在效用扭转特定的负面症状和认知缺陷。我们现在提出一系列研究，其中我们将优化高选择性 mGlu1 PAM，适用于临床前概念验证研究，并且具有所需的特性，以便随后能够进行高级 IND 支持研究和临床开发。