Laboratory of Antiepileptic Drug Discovery, Ascension St. Vincent, Indianapolis, IN, USA; Department of Chemistry & Biochemistry, Milwaukee Institute of Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, USA; RespireRx Pharmaceuticals Inc, Glen Rock, NJ, USA.
Department of Chemistry & Biochemistry, Milwaukee Institute of Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
Pharmacol Biochem Behav. 2022 Sep;219:173446. doi: 10.1016/j.pbb.2022.173446. Epub 2022 Aug 17.
Pharmacological modulation of glutamate has long been considered to be of immense therapeutic utility. The metabotropic glutamate receptors (mGluRs) are potential targets for safely altering glutamate-driven excitation. Data support the potential therapeutic use of mGluR modulators in the treatment of anxiety, depression, schizophrenia, and other psychiatric disorders, pain, epilepsy, as well as neurodegenerative and neurodevelopmental disorders. For each of the three mGluR groups, compounds have been constructed that produce either potentiation or functional blockade. PET ligands for mGlu5Rs have been studied in a range of patient populations and several mGlu5R antagonists have been tested for potential efficacy in patients including mavoglurant, diploglurant, basimglurant, GET 73, and ADX10059. Efficacy with mGlu5R antagonists has been reported in trials with patients with gastroesophageal reflux disease; data from patients with Parkinson's disease or Fragile X syndrome have not been as robust as hoped. Fenobam was approved for use as an anxiolytic prior to its recognition as an mGlu5R antagonist. mGlu2/3R agonists (pomaglumated methionil) and mGlu2R agonists (JNJ-40411813, AZD 8529, and LY2979165) have been studied in patients with schizophrenia with promising but mixed results. Antagonists of mGlu2/3Rs (decoglurant and TS-161) have been studied in depression where TS-161 has advanced into a planned Phase 2 study in treatment-resistant depression. The Group III mGluRs are the least developed of the mGluR receptor targets. The mGlu4R potentiator, foliglurax, did not meet its primary endpoint in patients with Parkinson's disease. Ongoing efforts to develop mGluR-targeted compounds continue to promise these glutamate modulators as medicines for psychiatric and neurological disorders.
谷氨酸的药理学调节长期以来被认为具有巨大的治疗效用。代谢型谷氨酸受体（mGluRs）是安全改变谷氨酸驱动兴奋的潜在靶点。数据支持 mGluR 调节剂在治疗焦虑、抑郁、精神分裂症和其他精神障碍、疼痛、癫痫以及神经退行性和神经发育性疾病中的潜在治疗用途。对于三个 mGluR 组中的每一个，都已经构建了产生增效或功能阻断的化合物。mGlu5R 的 PET 配体已经在一系列患者人群中进行了研究，并且已经测试了几种 mGlu5R 拮抗剂在包括 mavoglurant、diploglurant、basimglurant、GET 73 和 ADX10059 在内的患者中的潜在疗效。在胃食管反流病患者的试验中报告了 mGlu5R 拮抗剂的疗效；来自帕金森病或脆性 X 综合征患者的数据并不像预期的那样稳健。芬诺班在被确认为 mGlu5R 拮抗剂之前被批准用于焦虑症。mGlu2/3R 激动剂（pomaglumated methionil）和 mGlu2R 激动剂（JNJ-40411813、AZD 8529 和 LY2979165）已在精神分裂症患者中进行了研究，结果喜忧参半。mGlu2/3R 拮抗剂（decoglurant 和 TS-161）已在抑郁症患者中进行了研究，其中 TS-161 已进入治疗抵抗性抑郁症的计划 2 期研究。III 组 mGluRs 是 mGluR 受体靶标中开发最少的。在帕金森病患者中，mGlu4R 增效剂 foliglurax 未达到其主要终点。开发 mGluR 靶向化合物的持续努力继续承诺这些谷氨酸调节剂作为治疗精神和神经障碍的药物。
