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，选择性正变构 代谢型谷氨酸（mGlu）受体的mGlu 1亚型的调节剂（PAM）具有激动人心的潜力， 治疗精神分裂症的新方法。我们发现，高选择性mGlu1 PAM发挥其 在动物模型中通过选择性抑制纹状体中的多巴胺（DA）释放产生抗精神病样作用， 不在纹状体外区域，在那里抑制DA信号可能会导致现有的不良影响。 抗精神病药此外，我们提出了令人兴奋的新数据，表明mGlu1 PAM具有特异性， 前额叶皮层（PFC）内的活动，可以逆转特定皮层的病理生理变化， 在精神分裂症患者中被破坏的回路，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信号传导的作用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， 特定皮层回路的病理生理变化。现在重要的是优化高选择性 mGlu1 PAM适用于推进临床开发，以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用途。我们最近做了一个重大的 在发现和优化多种高选择性mGlu1 PAM方面取得了突破， 比如财产这些化合物提供了令人兴奋的新药物线索，可以为重点研究提供基础。 努力优化适合推进临床前和临床开发的新型mGlu1 PAM。 我们已经非常成功地优化了其他mGlu受体的多种选择性配体， 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 使我们处于一个非常有利的位置，以优化选择性mGlu1 PAM作为候选药物治疗 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 逆转特定的阴性症状和认知缺陷。我们现在提出一系列研究， 我们将优化适用于临床前概念验证研究的高选择性mGlu1 PAM， 所需的特性，以便随后可以进行先进的IND支持研究和临床开发。

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.