Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Prog Mol Biol Transl Sci. 2013;115:61-121. doi: 10.1016/B978-0-12-394587-7.00002-6.
The metabotropic glutamate receptors (mGlus) mediate a neuromodulatory role throughout the brain for the major excitatory neurotransmitter, glutamate. Seven of the eight mGlu subtypes are expressed within the CNS and are attractive targets for a variety of psychiatric and neurological disorders including anxiety, depression, schizophrenia, Parkinson's disease, and Fragile X syndrome. Allosteric modulation of these class C 7-transmembrane spanning receptors represents a novel approach to facilitate development of mGlu subtype-selective probes and therapeutics. Allosteric modulators that interact with sites topographically distinct from the endogenous ligand-binding site offer a number of advantages over their competitive counterparts. In particular for CNS therapeutics, allosteric modulators have the potential to maintain the spatial and temporal aspects of endogenous neurotransmission. The past 15 years have seen the discovery of numerous subtype-selective allosteric modulators for the majority of the mGlu family members, including positive, negative, and neutral allosteric modulators, with a number of mGlu allosteric modulators now in clinical trials.
代谢型谷氨酸受体（mGluRs）在整个大脑中对主要的兴奋性神经递质谷氨酸发挥神经调质作用。8 种 mGlu 亚型中有 7 种在中枢神经系统中表达，是各种精神和神经疾病的有吸引力的靶点，包括焦虑、抑郁、精神分裂症、帕金森病和脆性 X 综合征。这些 C 类 7 次跨膜受体的变构调节代表了促进 mGlu 亚型选择性探针和治疗药物开发的新方法。与内源性配体结合位点在拓扑上不同的变构调节剂与竞争性对应物相比具有许多优势。特别是对于中枢神经系统治疗药物，变构调节剂有可能维持内源性神经传递的空间和时间方面。在过去的 15 年中，已经发现了许多针对大多数 mGlu 家族成员的亚型选择性变构调节剂，包括正、负和中性变构调节剂，现在有许多 mGlu 变构调节剂正在临床试验中。
