Functions of Metabotropic Glutamate Receptor Subtypes

描述（由申请人提供）：高选择性阳性变构调节剂（pam）可增加代谢性谷氨酸（mGlu）受体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，目前正在推进PD患者的临床试验。mGlu4 PAMs的抗帕金森活性是由这些药物在大脑中称为纹状体-苍白叶突触的特定突触的活性介导的。mGlu4是纹状体-苍白质突触突触前末端唯一的mGlu4受体亚型，迄今为止鉴定的所有mGlu4 pam都能够增加这些mGlu4同质受体的活性。最近的研究表明，除了抗帕金森病作用外，一些mGlu4激活剂在啮齿动物模型中也具有抗精神病和抗焦虑作用。有趣的是，mGlu4和mGlu2在大脑突触上共定位，这可能对mGlu4 pam的其他作用很重要。此外，最近的细胞系研究表明，mGlu4和mGlu2具有形成mGlu2/4异源二聚体的潜力，这些异源二聚体由每种mGlu受体亚型的一个亚基组成。这就提出了mGlu4和mGlu2在特定脑回路中作为mGlu2/4异源二聚体起作用的可能性。虽然mGlu4 PAMs在这些突触和其他突触中的作用对抗帕金森效应并不重要，但在啮齿动物模型中观察到的抗精神病和抗焦虑活性的疗效中，这些通路的传输调节可能是关键。我们进行了广泛的初步研究，发现mGlu4 PAMs在单独表达时选择性地增加了mGlu4的活性，而当mGlu4与mGlu2共表达时则没有。此外，我们的初步数据表明，选择性增强mGlu4同质体反应的mGlu4 PAMs与mGlu2/4 PAMs相比，对特定中枢神经系统突触的突触传递具有不同的影响，并且这两组化合物在啮齿动物抗精神病和抗焦虑样活性模型中可能具有不同的作用。我们现在提出了一系列的研究，在这些研究中，我们将严格检验mGlu4同质体和mGlu2/4异源二聚体具有不同的药理学特征的假设，以及不同的靶向mGlu4同质体和异源体形式的调节剂在已确定的脑回路和用于预测抗帕金森病、抗精神病和抗糖尿病的啮齿动物模型中的作用存在根本差异

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.