Article
作者: Eddins, Donnie M ; Perkins, James J ; Manley, Peter J ; Converso, Antonella ; Liang, Yuexia ; Lu, Bing ; Wai, Jenny Miu-Chun ; Dubost, David C ; Zhu, Hong ; Puri, Vanita ; Hurzy, Danielle M ; Fillgrove, Kerry L ; Meng, Zhaoyang ; Manikowski, Jesse J ; Hayashi, Ikuo ; Uebele, Victor N ; Ma, Lei ; Shu, Youheng ; Ward, Gwendolyn J ; Frie, Jessica L ; Hanney, Barbara ; Kern, Jonathan T ; Vardigan, Joshua D ; Han, Yongxin ; Bungard, Christopher J ; Schachter, Joel B ; O'Brien, Julie ; Uslaner, Jason M ; Drolet, Robert E ; Bhandari, Neetesh ; Rudd, Michael T ; Cosden, Mali L ; Meissner, Robert S ; de Leon, Pablo ; Yang, Zhi-Qiang
Glutamate plays a key role in cognition and mood, and it has been shown that inhibiting ionotropic glutamate receptors disrupts cognition, while enhancing ionotropic receptor activity is pro-cognitive. One approach to elevating glutamatergic tone has been to antagonize presynaptic metabotropic glutamate receptor 2 (mGluR2). A desire for selectivity over the largely homologous mGluR3 motivated a strategy to achieve selectivity through the identification of mGluR2 negative allosteric modulators (NAMs). Extensive screening and optimization efforts led to the identification of a novel series of 4-arylquinoline-2-carboxamides. This series was optimized for mGluR2 NAM potency, clean off-target activity, and desirable physical properties, which resulted in the identification of improved C4 and C7 substituents. The initial lead compound from this series was Ames-positive in a single strain with metabolic activation, indicating that a reactive metabolite was likely responsible for the genetic toxicity. Metabolic profiling and Ames assessment across multiple analogs identified key structure-activity relationships associated with Ames positivity. Further optimization led to the Ames-negative mGluR2 negative allosteric modulator MK-8768.
