第二代代谢型谷氨酸受体负变构调节剂探针的研发
Development of a Second Generation mGlu NAM Probe
作者信息
Wenthur Cody, Daniels J. Scott, Morrison Ryan, Engers Julie L., Niswender Colleen M., Conn P. Jeffrey, Lindsley Craig W.
机构信息
Vanderbilt Specialized Chemistry Center, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center
Herein we report the discovery and structure activity relationship (SAR) of a novel, second generation metabotropic glutamate receptor 3 (mGlu) negative allosteric modulator (NAM) probe (ML337) with >50-fold selectivity versus mGlu (IC >30 μM). The mGlu NAM was discovered via an iterative parallel synthesis optimization of the first generation mGlu NAM ML289, that was only ~15-fold selective. This mGlu NAM (60204017, ML337) displays an IC value of 592 nM and is inactive (>30 μM) on mGlu (as well as mGlu) and clean in a Ricerca ancillary pharmacology panel. ML337 possesses favorable physiochemical properties, a good dystrophia myotonica protein kinase (DMPK) profile and is centrally penetrant. Thus, ML337 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第二代代谢型谷氨酸受体3（mGlu）负变构调节剂（NAM）探针（ML337）的发现及其构效关系（SAR），该探针对mGlu具有大于50倍的选择性（IC>30μM）。该mGlu NAM是通过对第一代mGlu NAM ML289进行迭代平行合成优化而发现的，第一代mGlu NAM的选择性仅约为15倍。这种mGlu NAM（60204017，ML337）的IC值为592 nM，对mGlu（以及mGlu）无活性（>30μM），并且在Ricerca辅助药理学面板中表现纯净。ML337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，并且能够穿透中枢。因此，ML337是研究mGlu非竞争性拮抗作用的同类最佳探针。
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