Sheffler Douglas J, Gregory Karen J, Rook Jerri M, Conn P Jeffrey
Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Adv Pharmacol. 2011;62:37-77. doi: 10.1016/B978-0-12-385952-5.00010-5.
The development of receptor subtype-selective ligands by targeting allosteric sites of G protein-coupled receptors (GPCRs) has proven highly successful in recent years. One GPCR family that has greatly benefited from this approach is the metabotropic glutamate receptors (mGlus). These family C GPCRs participate in the neuromodulatory actions of glutamate throughout the CNS, where they play a number of key roles in regulating synaptic transmission and neuronal excitability. A large number of mGlu subtype-selective allosteric modulators have been identified, the majority of which are thought to bind within the transmembrane regions of the receptor. These modulators can either enhance or inhibit mGlu functional responses and, together with mGlu knockout mice, have furthered the establishment of the physiologic roles of many mGlu subtypes. Numerous pharmacological and receptor mutagenesis studies have been aimed at providing a greater mechanistic understanding of the interaction of mGlu allosteric modulators with the receptor, which have revealed evidence for common allosteric binding sites across multiple mGlu subtypes and the presence for multiple allosteric sites within a single mGlu subtype. Recent data have also revealed that mGlu allosteric modulators can display functional selectivity toward particular signal transduction cascades downstream of an individual mGlu subtype. Studies continue to validate the therapeutic utility of mGlu allosteric modulators as a potential therapeutic approach for a number of disorders including anxiety, schizophrenia, Parkinson's disease, and Fragile X syndrome.
近年来，通过靶向G蛋白偶联受体（GPCRs）的变构位点来开发受体亚型选择性配体已被证明非常成功。代谢型谷氨酸受体（mGlus）这个GPCR家族从这种方法中受益匪浅。这些C类GPCR在整个中枢神经系统中参与谷氨酸的神经调节作用，在调节突触传递和神经元兴奋性方面发挥着许多关键作用。已经鉴定出大量mGlu亚型选择性变构调节剂，其中大多数被认为结合在受体的跨膜区域内。这些调节剂可以增强或抑制mGlu的功能反应，并且与mGlu基因敲除小鼠一起，进一步明确了许多mGlu亚型的生理作用。大量的药理学和受体诱变研究旨在更深入地了解mGlu变构调节剂与受体的相互作用机制，这些研究揭示了多个mGlu亚型存在共同变构结合位点以及单个mGlu亚型内存在多个变构位点的证据。最近的数据还表明，mGlu变构调节剂可以对单个mGlu亚型下游的特定信号转导级联反应表现出功能选择性。研究继续验证mGlu变构调节剂作为包括焦虑症、精神分裂症、帕金森病和脆性X综合征在内的多种疾病的潜在治疗方法的治疗效用。
