Metabotropic Glutamate Receptors in Basal Ganglia

描述（由申请人提供）：基于多巴胺替代策略的帕金森病（PD）传统治疗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丧失疗效。正因为如此，大量的努力已经集中在发展的电路和基底神经节的功能的详细了解，希望开发新的治疗方法，恢复正常的基底神经节功能的患者患有PD。我们对代谢型谷氨酸受体（mGluRs）的功能和mGluR亚型在基底神经节中的分布的理解取得了令人兴奋的进展，这表明该受体家族的成员可以作为有效治疗PD的新型治疗药物的靶点。我们已经进行了大量的研究，表明mGlu 4受体亚型可能是特别有吸引力的一个新的目标，用于治疗PD。mGlu 4定位于纹状体和苍白球之间的突触（纹状体-苍白球突触）中的突触前末梢上。这是基底神经节运动回路中的关键突触，先前的研究表明，减少该突触处的传递可能对PD患者具有治疗效果。我们已经表明，激活mGlu 4减少在纹状体-GP突触的传输。此外，我们目前的数据表明，mGlu 4的激动剂可能有抗帕金森病的作用，在几个啮齿动物模型的PD。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且还具有适当药物样性质的选择性激动剂是极其困难的。我们有令人兴奋的初步研究，提供了一种新的方法来开发激活mGlu 4的小分子。我们发现了一种名为PHCCC的新型化合物，它不直接激活mGlu 4，但显著增强谷氨酸或L-AP 4对受体的激活。此外，我们的初步研究表明，mGlu 4的变构增效剂可能具有与传统mGlu 4激动剂相似的抗帕金森病作用。在拟议的研究中，我们将严格测试的假设，即mGlu 4是本地化的关键纹状体终端，激活这种受体选择性地减少在纹状体突触的传输。此外，我们将测试的假设，该受体的激动剂或变构增效剂可以提供姑息性缓解在啮齿动物模型的PD的GP的行动。

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.