Gasparini Fabrizio, Kuhn Rainer, Pin Jean-Philippe
Nervous System Research, Novartis Pharma AG, Postfach, 4002, Basel, Switzerland.
Curr Opin Pharmacol. 2002 Feb;2(1):43-9. doi: 10.1016/s1471-4892(01)00119-9.
Recent drug discovery programs aimed at identifying selective metabotropic mGlu receptor ligands by high-throughput functional screening efforts have revealed subtype-selective allosteric modulators of mGlu1 and mGlu5 receptors that are structurally unrelated to glutamate. In contrast to competitive ligands, which bind to the glutamate binding site located in the large N-terminal extracellular domain, these modulators act as non-competitive antagonists, inverse agonists or positive modulators by binding to specific residues in the seven-transmembrane domain. More recent studies to assess the potential of these compounds in in vivo models of nervous system disorders have implicated the mGlu5 receptor subtype as a potentially important therapeutic target for inflammatory pain, anxiety, Parkinson's disease and drug abuse, and mGlu1 and mGlu5 receptors as potential targets for anticonvulsant and neuroprotective therapies. Very recent findings indicate an important regulatory role for intracellular proteins interacting with metabotropic glutamate receptors, which might constitute novel drug targets for modulating metabotropic glutamate receptor activity.
近期旨在通过高通量功能筛选来鉴定选择性代谢型谷氨酸受体（mGlu）配体的药物研发项目，已发现了与谷氨酸结构不相关的mGlu1和mGlu5受体亚型选择性变构调节剂。与结合位于大的N端细胞外结构域中的谷氨酸结合位点的竞争性配体不同，这些调节剂通过与七跨膜结构域中的特定残基结合，作为非竞争性拮抗剂、反向激动剂或正向调节剂发挥作用。最近评估这些化合物在神经系统疾病体内模型中的潜力的研究表明，mGlu5受体亚型是炎性疼痛、焦虑症、帕金森病和药物滥用的潜在重要治疗靶点，而mGlu1和mGlu5受体是抗惊厥和神经保护疗法的潜在靶点。最新研究结果表明，细胞内蛋白与代谢型谷氨酸受体相互作用具有重要的调节作用，这可能构成调节代谢型谷氨酸受体活性的新型药物靶点。
