Functions of Metabotropic Glutamate Receptor Subtypes

代谢型谷氨酸受体亚型的功能

• 批准号: 8686445
• 负责人: P Jeffrey Conn
• 金额: $ 48.53万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8686445
• 关键词: Address; Animal Model; Anti-Anxiety Agents; Antiparkinson Agents; Antipsychotic Agents; Anxiety Disorders; Behavioral; Brain; Cell Line; Cells; Complex; Corpus striatum structure; Coupled; Data; Drug Targeting; Energy Transfer; Exhibits; Fluorescence Resonance Energy Transfer; G Protein-Coupled Receptor Genes; GTP-Binding Proteins; Knockout Mice; Ligands; Measures; Mediating; Metabotropic Glutamate Receptors; Methods; Names; Neurotransmitter Receptor; Parkinson Disease; Pathway interactions; Patients; Pharmaceutical Preparations; Presynaptic Terminals; Proteins; Recombinants; Relative (related person); Rodent Model; Schizophrenia; Series; Slice; Specificity; Synapses; Synaptic Transmission; System; Testing; Therapeutic Agents; Time; base; in vivo; insight; monomer; novel strategies; patch clamp; protein activation; public health relevance; receptor; research clinical testing; response; transmission process

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.

描述（由申请人提供）：增加代谢型谷氨酸（mGlu）受体mGlu 4亚型活性的高选择性正变构调节剂（PAM）在帕金森病（PD）啮齿动物模型中具有稳健的疗效，目前正在推进PD患者的临床试验。mGlu 4 PAM的抗帕金森病活性由这些药剂在脑中称为纹状体-苍白球突触的特定突触处的活性介导。mGlu 4是纹状体-苍白球突触突触前末梢中唯一的mGlu受体亚型，并且迄今为止鉴定的所有mGlu 4 PAM都能够增加这些mGlu 4同源受体的活性。最近的研究表明，除了抗帕金森病作用外，一些mGlu 4激活剂在预测抗精神病和抗焦虑作用的啮齿动物模型中也有效。有趣的是，mGlu 4和mGlu 2共同定位于大脑中的突触，这可能对mGlu 4 PAM的这些其他作用很重要。此外，最近在细胞系中的研究表明，mGlu 4和mGlu 2具有形成mGlu 2/4异二聚体的潜力，所述异二聚体由这些mGlu受体亚型中的每一种的一个亚基组成。这提出了mGlu 4和mGlu 2作为mGlu 2/4异源二聚体在特定识别的脑回路中起作用的可能性。虽然mGlu 4 PAM在这些和其他突触处的作用对于抗帕金森病作用不是关键的，但这些通路中的传递调节对于在预测抗精神病药和抗焦虑药活性的啮齿动物模型中观察到的疗效可能是关键的。我们提出了广泛的初步研究，其中我们已经确定了mGlu 4 PAM，选择性地增加mGlu 4的活性时，单独表达，但不当mGlu 4与mGlu 2共表达。此外，我们的初步数据表明，mGlu 4 PAM，选择性地加强在mGlu 4同聚体的反应有不同的影响，在特定的中枢神经系统突触的突触传递比mGlu 2/4 PAM，属于这两个组的化合物可能有不同的影响，在抗精神病和抗焦虑样活性的啮齿动物模型。我们现在提出了一系列研究，其中我们将严格检验以下假设，即mGlu 4同聚体和mGlu 2/4异二聚体具有不同的药理学特征，并且差异靶向mGlu 4同聚体与异聚体形式的调节剂在鉴定的脑回路中以及在用于预测抗帕金森病、抗精神病和抗抑郁症的啮齿动物模型中的作用具有根本差异。 抗焦虑功效如果mGlu 4的同聚体和异聚体形式可以被药物样分子选择性地靶向，这将提供关键的新见解，这将影响目前的努力， 开发mGlu 4 PAM作为治疗剂。除了通过靶向mGlu 4同聚体治疗PD实现更高的特异性外，这些研究还提出了一种令人兴奋的可能性，即选择性靶向mGlu 2/4异聚体受体可以为治疗精神分裂症和焦虑症提供一种新方法。