Metabotropic Glutamate Receptors in Basal Ganglia

描述(申请人提供)：基于多巴胺替代策略的治疗帕金森病(PD)的传统疗法最终在大多数患者中失败，原因是严重的不良反应和随着疾病进展而失去疗效。正因为如此，人们一直致力于对基底节的回路和功能进行详细的了解，以期开发新的治疗方法来恢复帕金森病患者的正常基底节功能。我们对代谢性谷氨酸受体(MGluRs)的功能和mGluR亚型在基底节的分布的了解取得了令人兴奋的进展，表明该受体家族的成员可以作为新的治疗药物的靶点，这些药物将有效地治疗PD。我们已经进行了许多研究，表明mGlu4受体亚型作为治疗帕金森病的新靶点可能特别有吸引力。MGlu4定位于纹状体和苍白球(纹状-苍白球突触)之间突触前终末。这是基底节运动回路中的一个关键突触，先前的研究表明，减少这一突触的传递可能对帕金森病患者有治疗作用。我们已经证明，激活mGlu4减少了纹状体-GP突触的传递。此外，我们提出的数据表明，mGlu4激动剂可能在几种帕金森病啮齿动物模型中具有抗帕金森病的作用。虽然这些结果令人鼓舞，但开发对特定mGlu受体亚型具有高亲和力的选择性激动剂，同时又具有适当的药物样特性是极其困难的。我们有令人兴奋的初步研究，为开发激活mGlu4的小分子提供了一种新的方法。我们发现了一种新的化合物，称为PHCCC，它不直接激活mGlu4，但显著增强谷氨酸或L-AP4对mGlu4受体的激活。此外，我们的初步研究表明，mGlu4的变构增强剂可能具有与传统mGlu4激动剂相似的抗帕金森病作用。在拟议的研究中，我们将严格检验这一假设，即mGlu4定位于关键的纹状体终末，并且该受体的激活选择性地减少纹状体桥叶突触的传递。此外，我们将检验这一受体的激动剂或变构增强剂可以通过作用于GP而在PD啮齿动物模型中提供姑息性缓解的假设。

DESCRIPTION (provided by applicant): Traditional therapies for treatment of Parkinson's disease (PD) based on dopamine replacement strategies eventually fail in most patients due to serious adverse effects and loss of efficacy with disease progression. Because of this, a great deal of effort has been focused on developing a detailed understanding of the circuitry and function of the basal ganglia in hopes of developing novel therapeutic approaches for restoring normal basal ganglia function in patients suffering from PD. Exciting advances in our understanding of the function of metabotropic glutamate receptors (mGluRs) and the distribution of mGluR subtypes in the basal ganglia suggest that members of this receptor family could serve as targets for novel therapeutic agents that would be effective in treatment of PD. We have performed a number of studies that suggest that the mGlu4 receptor subtype may be particularly attractive as a novel target for treatment of PD. mGlu4 is localized on presynaptic terminals in the synapse between the striatum an the globus pallidus (the striato-pallidal synapse). This is a critical synapse in the basal ganglia motor circuit and previous studies suggest that reduction of transmission at this synapse could have a therapeutic effect in PD patients. We have shown that activation of mGlu4 reduces transmission at the striato-GP synapse. Furthermore, we present data suggesting that agonists of mGlu4 may have an antiparkinsonian effect in several rodent models of PD. While these results are encouraging, it has been extremely difficult to develop selective agonists with high affinity for specific mGlu receptor subtypes that also have appropriate drug-like properties. We have exciting preliminary studies that provide a novel approach to developing small molecules that activate mGlu4. We have discovered a novel compound termed PHCCC that does not activate mGlu4 directly but dramatically potentiates activation of the receptor by glutamate or L-AP4. Furthermore, our preliminary studies suggest that allosteric potentiator of mGlu4 may have antiparkinsonian actions similar to those observed with traditional mGlu4 agonists. In the proposed studies we will rigorously test the hypothesis that mGlu4 is localized on critical striatal terminals and that activation of this receptor selectively reduces transmission at the Striatopallidal synapse. Furthermore, we will test the hypothesis that agonists or allosteric potentiators of this receptor can provide palliative relief in rodent models of PD by actions in the GP.