基于亲代谢型谷氨酸受体（mGlu）正变构调节剂（PAM）筛选结果开发首个选择性mGlu负变构调节剂（NAM）
Development of the First Selective mGlu NAM from an mGlu PAM Hit
作者信息
Sheffler Douglas J., Wenthur Cody J., Brunner Joshua A., Daniels J. Scott, Morrison Ryan D., Blobaum Anna L., Dawson Eric S., Engers Julie L., Niswender Colleen M., Conn P. Jeffrey, Lindsley Craig W.
Herein we report the discovery and structure activity relationship (SAR) of a novel metabotropic glutamate receptor 3 (mGlu) negative allosteric modulators (NAM) probe (ML289) with 15-fold selectivity versus mGlu (IC >10 μM). The mGlu NAM was discovered via a ‘molecular switch’ from a closely related, potent (EC = 197 nM) mGlu positive allosteric modulator (PAM), CID 16000100. This mGlu NAM (CID 56587994, ML289) displays an IC value of 649 nM and is inactive on mGlu (>30 μM) and clean in a Ricerca ancillary pharmacology panel. ML289 possesses favorable physiochemical properties, a good dystrophia myotonica protein kinase (DMPK) profile and is centrally penetrant. Thus, ML289 is a best-in-class and probe for studying non-competitive antagonism of mGlu.
在此，我们报告了一种新型代谢型谷氨酸受体3（mGlu）负变构调节剂（NAM）探针（ML289）的发现及其构效关系（SAR），该探针对mGlu具有15倍的选择性（IC>10 μM）。该mGlu NAM是通过从一种密切相关的、强效的（EC=197 nM）mGlu正变构调节剂（PAM）CID 16000100进行“分子开关”而发现的。这种mGlu NAM（CID 56587994，ML289）的IC值为649 nM，对mGlu无活性（>30 μM），在Ricerca辅助药理学面板中表现纯净。ML289具有良好的物理化学性质、良好的强直性肌营养不良蛋白激酶（DMPK）特征且能穿透中枢。因此，ML289是研究mGlu非竞争性拮抗作用的同类最佳探针。
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