943656-55-1Relevant articles and documents
Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators (PAMs): Tuning Deactivation Kinetics via Structure-Based Design
Volgraf, Matthew,Sellers, Benjamin D.,Jiang, Yu,Wu, Guosheng,Ly, Cuong Q.,Villemure, Elisia,Pastor, Richard M.,Yuen, Po-Wai,Lu, Aijun,Luo, Xifeng,Liu, Mingcui,Zhang, Shun,Sun, Liang,Fu, Yuhong,Lupardus, Patrick J.,Wallweber, Heidi J.A.,Liederer, Bianca M.,Deshmukh, Gauri,Plise, Emile,Tay, Suzanne,Reynen, Paul,Herrington, James,Gustafson, Amy,Liu, Yichin,Dirksen, Akim,Dietz, Matthias G. A.,Liu, Yanzhou,Wang, Tzu-Ming,Hanson, Jesse E.,Hackos, David,Scearce-Levie, Kimberly,Schwarz, Jacob B.
, p. 2760 - 2779 (2016/04/10)
The N-methyl-d-aspartate receptor (NMDAR) is a Na+ and Ca2+ permeable ionotropic glutamate receptor that is activated by the coagonists glycine and glutamate. NMDARs are critical to synaptic signaling and plasticity, and their dysfunction has been implicated in a number of neurological disorders, including schizophrenia, depression, and Alzheimer's disease. Herein we describe the discovery of potent GluN2A-selective NMDAR positive allosteric modulators (PAMs) starting from a high-throughput screening hit. Using structure-based design, we sought to increase potency at the GluN2A subtype, while improving selectivity against related α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). The structure-activity relationship of channel deactivation kinetics was studied using a combination of electrophysiology and protein crystallography. Effective incorporation of these strategies resulted in the discovery of GNE-0723 (46), a highly potent and brain penetrant GluN2A-selective NMDAR PAM suitable for in vivo characterization.
