Functions of Metabotropic Glutamate Receptor Subtypes

描述(由申请人提供)：高选择性正变构调节剂(PAM)可增加代谢性谷氨酸(MGlu)受体的mGlu4亚型的活性，在帕金森病(PD)的啮齿动物模型中具有强大的疗效，目前正被推进用于PD患者的临床测试。MGlu4 PAM的抗帕金森病活性是通过这些药物在大脑中称为纹状-苍白球突触的特定突触上的活性而介导的。MGlu4是纹状-苍白球突触突触前终末中唯一的mGlu受体亚型，迄今发现的所有mGlu4 PAM都能增加这些mGlu4同源受体的活性。最近的研究表明，除了抗帕金森症的作用外，一些mGlu4激动剂在预测抗精神病和抗焦虑效果的啮齿动物模型中也有疗效。有趣的是，mGlu4和mGlu2共同定位于大脑中的突触，这可能对mGlu4 PAM的其他作用很重要。此外，最近在细胞系中的研究表明，mGlu4和mGlu2有可能形成mGlu2/4异二聚体，由这些mGlu受体亚型的一个亚基组成。这增加了mGlu4和mGlu2作为mGlu2/4异源二聚体在特定的已识别大脑回路中发挥作用的可能性。虽然mGlu4 PAM在这些和其他突触上的作用对抗帕金森症的作用并不关键，但这些通路中传递的调节可能是在预测抗精神病和抗焦虑活性的啮齿动物模型中观察到的疗效的关键。我们提供了大量的初步研究，在这些研究中，我们发现mGlu4 PAM在单独表达时选择性地增加mGlu4的活性，但当mGlu4与mGlu2共表达时不能选择性地增加mGlu4的活性。此外，我们的初步数据表明，选择性增强mGlu4同聚体反应的mGlu4 PAM对特定中枢神经系统突触传递的影响不同于mGlu2/4 PAM，这两组化合物在抗精神病和抗焦虑样活性的啮齿动物模型中可能具有不同的作用。我们现在提出一系列研究，在这些研究中，我们将严格检验这一假设，即mGlu4同聚体和mGlu2/4异二聚体具有不同的药理学特征，并且针对mGlu4同聚体和异构体形式的不同调节剂在已识别的大脑回路和用于预测抗帕金森病、抗精神病药物和抗精神病药物的啮齿动物模型中的作用存在根本差异。 抗焦虑功效。如果同构体和异构体的mGlu4可以选择性地被类药物分子靶向，这将提供关键的新见解，将影响当前的努力 开发mGlu4 PAM作为治疗剂。除了通过靶向mGlu4同聚体治疗帕金森病获得更高的特异性外，这些研究还提出了一种令人兴奋的可能性，即选择性靶向mGlu2/4异构体受体可能为精神分裂症和焦虑症的治疗提供一种新的方法。

DESCRIPTION (provided by applicant): Highly selective positive allosteric modulators (PAMs) that increase activity of the mGlu4 subtype of metabotropic glutamate (mGlu) receptor have robust efficacy in rodent models of Parkinson's disease (PD) and are now being advanced for clinical testing in PD patients. The antiparkinsonian activity of mGlu4 PAMs is mediated by activity of these agents at a specific synapse in brain called the striato-pallidal synapse. mGlu4 is the only mGlu receptor subtype in presynaptic terminals at striato-pallidal synapses and all mGlu4 PAMs identified to date are capable of increasing activity of these mGlu4 homomeric receptors. More recent studies suggest that, in addition to antiparkinsonian effects, some mGlu4 activators have efficacy in rodent models that predict antipsychotic and antianxiety effects. Interestingly, mGlu4 and mGlu2 are co-localized at synapses in the brain that could be important for these other actions of mGlu4 PAMs. Furthermore, recent studies in cell lines suggest that mGlu4 and mGlu2 have the potential to form mGlu2/4 heterodimers that consist of one subunit of each of these mGlu receptor subtypes. This raises the possibility that mGlu4 and mGlu2 function as mGlu2/4 heterodimers in specific identified brain circuits. While actions of mGlu4 PAMs at these and other synapses are not critical for antiparkinsonian effects, modulation of transmission in these pathways may be critical for efficacy observed in rodent models that predict antipsychotic and anxiolytic activity. We present extensive preliminary studies in which we have identified mGlu4 PAMs that selectively increase activity of mGlu4 when expressed alone but not when mGlu4 is co-expressed with mGlu2. Furthermore, our preliminary data suggest that mGlu4 PAMs that selectively potentiate responses at mGlu4 homomers have different effects on synaptic transmission at specific CNS synapses than do mGlu2/4 PAMs and that compounds belonging to these two groups may have different effects in rodent models of antipsychotic and anxiolytic-like activity. We now propose a series of studies in which we will rigorously test the hypothesis that mGlu4 homomers and mGlu2/4 heterodimers have distinct pharmacological profiles and that modulators that differentially target the homomeric versus heteromeric forms of mGlu4 have fundamental differences in their effects in identified brain circuits and in rodent models used to predict antiparkinsonian, antipsychotic, and anxiolytic efficacy. If homomeric and heteromeric forms of mGlu4 can be selectively targeted by drug-like molecules, this will provide critical new insights that will influence current efforts to develop mGlu4 PAMs as therapeutic agents. In addition to achieving greater specificity by targeting mGlu4 homomers for treatment of PD, these studies raise the exciting possibility that selectively targeting mGlu2/4 heteromeric receptors could provide a novel approach for treatment of schizophrenia and anxiety disorders.