Lindsley Craig W, Stauffer Shaun R
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Pharm Pat Anal. 2013 Jan;2(1):93-108. doi: 10.4155/ppa.12.82.
The mGlu5, a class C G-protein-coupled receptor and member of the group I mGlu receptor family, has been demonstrated to play a role in a number of therapeutic areas within the CNS, including schizophrenia, dementia, epilepsy, cognition, drug abuse, and fragile X syndrome. Small-molecule modulation of mGlu5 via positive allosteric modulators (PAMs) is being pursued as a promising approach for the treatment of schizophrenia and has been validated preclinically in a number of animal models. This article provides a brief historical overview of mGlu5 PAMs in the primary literature followed by a comprehensive overview of the patent literature since 2004. Schizophrenia is a complex disorder and although no mGlu5 PAMs have progressed into clinical trials in patients, the target continues to show promise as an attractive non-dopaminergic therapy. The successful development of mGlu5 PAMs for clinical testing must address several issues, including challenges associated with 'molecular switches', allosteric-agonist activity and stimulus bias.
代谢型谷氨酸受体5（mGlu5）是C类G蛋白偶联受体，属于I组代谢型谷氨酸受体家族成员，已被证明在中枢神经系统的多个治疗领域发挥作用，包括精神分裂症、痴呆、癫痫、认知、药物滥用和脆性X综合征。通过正变构调节剂（PAM）对mGlu5进行小分子调节，正被作为一种有前景的精神分裂症治疗方法进行研究，并且已在多种动物模型中得到临床前验证。本文首先对主要文献中mGlu5 PAM进行简要的历史概述，然后对2004年以来的专利文献进行全面概述。精神分裂症是一种复杂的疾病，虽然尚无mGlu5 PAM进入患者临床试验阶段，但该靶点作为一种有吸引力的非多巴胺能疗法仍显示出前景。成功开发用于临床试验的mGlu5 PAM必须解决几个问题，包括与“分子开关”、变构激动剂活性和刺激偏向相关的挑战。
