International Union of Basic and Clinical Pharmacology. CXI. Pharmacology, Signaling, and Physiology of Metabotropic Glutamate Receptors,Pharmacological Reviews

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International Union of Basic and Clinical Pharmacology. CXI. Pharmacology, Signaling, and Physiology of Metabotropic Glutamate Receptors
Pharmacological Reviews ( IF 19.3 ) Pub Date : 2021-01-01 , DOI: 10.1124/pr.119.019133
Karen J Gregory ₁ , Cyril Goudet ₁

Affiliation

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.

中文翻译：

国际基础和临床药理学联合会。CXI。代谢型谷氨酸受体的药理学、信号传导和生理学

代谢型谷氨酸 (mGlu) 受体对谷氨酸（哺乳动物大脑中的主要兴奋性神经递质）作出反应，介导一种对学习和记忆等高级大脑功能至关重要的调节作用。自 1992 年克隆第一个 mGlu 受体以来，已鉴定出八种亚型以及许多同种型和剪接变体。mGlu 受体是跨膜蛋白，属于 CG 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。过去三十年的协同药物发现工作产生了丰富的药理学工具，包括竞争性阻断或模拟谷氨酸作用或通过不同位点变构作用以增强或抑制受体活性的亚型选择性试剂。在此处，我们回顾了个体 mGlu 受体亚型的生理和病理生理作用，包括由每种亚型引起的细胞内信号转导的多效性。我们对原型和市售正构激动剂和拮抗剂以及变构调节剂（包括已进入临床试验的配体）的体外和体内药理学特性进行了全面分析。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选择性 mGlu 受体靶向疗法的合理设计。我们对原型和市售正构激动剂和拮抗剂以及变构调节剂（包括已进入临床试验的配体）的体外和体内药理学特性进行了全面分析。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选择性 mGlu 受体靶向疗法的合理设计。我们对原型和市售正构激动剂和拮抗剂以及变构调节剂（包括已进入临床试验的配体）的体外和体内药理学特性进行了全面分析。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选择性 mGlu 受体靶向疗法的合理设计。

更新日期：2020-12-24

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