Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia (K.J.G.) and Institut de Génomique Fonctionnelle (IGF), University of Montpellier, Centre National de la Recherche Scientifique (CNRS), Institut National de la Sante et de la Recherche Medicale (INSERM), Montpellier, France (C.G.)
Pharmacol Rev. 2021 Jan;73(1):521-569. doi: 10.1124/pr.119.019133.
Metabotropic glutamate (mGlu) receptors respond to glutamate, the major excitatory neurotransmitter in the mammalian brain, mediating a modulatory role that is critical for higher-order brain functions such as learning and memory. Since the first mGlu receptor was cloned in 1992, eight subtypes have been identified along with many isoforms and splice variants. The mGlu receptors are transmembrane-spanning proteins belonging to the class C G protein-coupled receptor family and represent attractive targets for a multitude of central nervous system disorders. Concerted drug discovery efforts over the past three decades have yielded a wealth of pharmacological tools including subtype-selective agents that competitively block or mimic the actions of glutamate or act allosterically via distinct sites to enhance or inhibit receptor activity. Herein, we review the physiologic and pathophysiological roles for individual mGlu receptor subtypes including the pleiotropic nature of intracellular signal transduction arising from each. We provide a comprehensive analysis of the in vitro and in vivo pharmacological properties of prototypical and commercially available orthosteric agonists and antagonists as well as allosteric modulators, including ligands that have entered clinical trials. Finally, we highlight emerging areas of research that hold promise to facilitate rational design of highly selective mGlu receptor-targeting therapeutics in the future. SIGNIFICANCE STATEMENT: The metabotropic glutamate receptors are attractive therapeutic targets for a range of psychiatric and neurological disorders. Over the past three decades, intense discovery efforts have yielded diverse pharmacological tools acting either competitively or allosterically, which have enabled dissection of fundamental biological process modulated by metabotropic glutamate receptors and established proof of concept for many therapeutic indications. We review metabotropic glutamate receptor molecular pharmacology and highlight emerging areas that are offering new avenues to selectively modulate neurotransmission.
代谢型谷氨酸受体（mGluR）对谷氨酸做出反应，谷氨酸是哺乳动物大脑中的主要兴奋性神经递质，介导了一种调节作用，对于学习和记忆等高级脑功能至关重要。自 1992 年首次克隆出 mGluR 以来，已经鉴定出 8 种亚型以及许多同工型和剪接变体。mGluR 是跨膜的跨膜蛋白，属于 C 类 G 蛋白偶联受体家族，是多种中枢神经系统疾病的有吸引力的靶标。在过去的三十年中，药物发现工作的协同努力产生了丰富的药理学工具，包括对各亚型具有选择性的药物，这些药物竞争性地阻断或模拟谷氨酸的作用，或者通过独特的位点变构作用增强或抑制受体活性。本文综述了各个 mGluR 亚型的生理和病理生理作用，包括每种亚型引起的细胞内信号转导的多效性。我们全面分析了原型和商业上可获得的变构激动剂和拮抗剂以及变构调节剂的体外和体内药理学特性，包括已进入临床试验的配体。最后，我们强调了新兴的研究领域，这些领域有望促进未来高度选择性的 mGluR 靶向治疗药物的合理设计。
代谢型谷氨酸受体是一系列精神和神经疾病的有吸引力的治疗靶标。在过去的三十年中，强烈的发现努力产生了各种药理学工具，这些工具要么竞争性地作用，要么变构作用，这使得对代谢型谷氨酸受体调节的基本生物学过程进行了剖析，并为许多治疗适应症确立了概念验证。我们综述了代谢型谷氨酸受体的分子药理学，并强调了提供新途径以选择性调节神经传递的新兴领域。
