Discovery of mGlu receptor PAMs for treatment of schizophrenia

最近的临床和临床前研究以及人类遗传学研究表明，选择性阳性变构 代谢性谷氨酸(MGlu)受体的mGlu1亚型的调节剂(PAM)具有作为 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 选择性抑制纹状体多巴胺释放在动物模型中的抗精神病药样作用 而不是在纹状体外区域，在那里抑制DA信号可能会导致现有的 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 前额叶皮质(PFC)内可逆转特定皮质病理生理变化的活动 精神分裂症患者的回路被扰乱，并可以逆转特定的认知和社会缺陷 啮齿动物模型。因此，mGlu1 PAM可以通过DA信号的作用提供强大的抗精神病疗效， 还可以改善精神分裂症患者的一些阴性症状和认知障碍 特定皮质环路的病理生理学变化。现在重要的是优化高度选择性 适合推进到临床开发的mGlu1 PAM，允许临床研究直接评估 这些化合物作为治疗精神分裂症的新策略的效用。我们最近做了一个重大的 具有优良药物的多种高选择性mGlu1 PAM的发现和优化取得突破 就像房产一样。这些化合物提供了令人兴奋的新药物线索，可以为 努力优化适合推进临床前和临床开发的新型mGlu1 PAM。 我们已经非常成功地优化了其他mGlu受体和其他受体的多个选择性配体 GPCR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 使我们处于一个极好的位置，可以优化选择性mGlu1 PAM作为治疗糖尿病的候选药物 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用途 在扭转特定的负面症状和认知缺陷方面。我们现在提出一系列研究，其中 我们将优化高度选择性的mGlu1 PAM，适用于临床前概念验证研究，并具有 所需的特性，以便它们随后可以被高级IND使能研究和临床开发。

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.