Gentry Patrick R., Kokubo Masaya, Bridges Thomas M., Daniels J. Scott, Niswender Colleen M., Smith Emery, Chase Peter, Hodder Peter S., Rosen Hugh, Conn P. Jeffrey, Engers Julie, Brewer Katrina A., Wood Michael R., Lindsley Craig W.
Vanderbilt University
Scripps Research Institute
A recently completed functional, high throughput screen of the Molecular Libraries Probe Production Center's Network (MLPCN) screening deck of ∼360,000 compounds conducted by Scripps Research Institute Molecular Screening Center (SRIMSC) against three of the five muscarinic receptor subtypes (M, M and M) provided a number of interesting hits. As this was the first time a directed effort had been undertaken to identify M selective leads, we were very pleased by the identification of nine M PAMs and nine M antagonists (or negative allosteric modulators, NAMs), despite the complete absence of M agonist hits. The most promising M inhibitor hit (CID 5189681), was quickly developed into a potent, selective and CNS penetrant probe molecule ML375 (hM NAM IC = 300 nM, hM ICs >30 μM) displaying enantioselective inhibition. Detailed molecular pharmacology studies demonstrated that ML375 is the first M NAM ever described, and ML375 show good rat and cyno pharmacokinetics to support studies in rodents and non-human primates.
斯克里普斯研究所分子筛选中心（SRIMSC）针对五个毒蕈碱受体亚型中的三个（M、M和M），对分子文库探针生产中心网络（MLPCN）约360,000种化合物的筛选库进行了一项最近完成的功能性高通量筛选，获得了一些有趣的命中化合物。由于这是首次有针对性地努力鉴定M选择性先导物，尽管完全没有M激动剂命中化合物，但我们对鉴定出9种M型正变构调节剂（PAMs）和9种M拮抗剂（或负变构调节剂，NAMs）感到非常高兴。最有前景的M抑制剂命中化合物（化合物识别号5189681）很快被开发成一种强效、选择性且可穿透中枢神经系统的探针分子ML375（人M型NAM的半数抑制浓度[IC] = 300 nM，人M型的IC>30 μM），表现出对映选择性抑制。详细的分子药理学研究表明，ML375是有史以来描述的首个M型NAM，并且ML375在大鼠和食蟹猴中显示出良好的药代动力学，以支持在啮齿动物和非人类灵长类动物中的研究。
