5I2N

Structure of the human GluN1/GluN2A LBD in complex with N-ethyl-7-{[2-fluoro-3-(trifluoromethyl)phenyl]methyl}-2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide (compound 29)

5I2N の概要

• エントリーDOI: 10.2210/pdb5i2n/pdb
• 関連するPDBエントリー: 5I2J 5I2K
• 分子名称: Glutamate receptor ionotropic, NMDA 2A, Glutamate receptor ionotropic, NMDA 1, CALCIUM ION, ... (8 entities in total)
• 機能のキーワード: nmda, receptor, glutamate, channel, transport protein
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Cell membrane; Multi-pass membrane protein: Q12879 Q05586
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 66206.48

構造登録者

Wallweber, H.J.A.,Lupardus, P.J. (登録日: 2016-02-09, 公開日: 2016-03-16, 最終更新日: 2024-11-06)

主引用文献

Volgraf, M.,Sellers, B.D.,Jiang, Y.,Wu, G.,Ly, C.Q.,Villemure, E.,Pastor, R.M.,Yuen, P.W.,Lu, A.,Luo, X.,Liu, M.,Zhang, S.,Sun, L.,Fu, Y.,Lupardus, P.J.,Wallweber, H.J.,Liederer, B.M.,Deshmukh, G.,Plise, E.,Tay, S.,Reynen, P.,Herrington, J.,Gustafson, A.,Liu, Y.,Dirksen, A.,Dietz, M.G.,Liu, Y.,Wang, T.M.,Hanson, J.E.,Hackos, D.,Scearce-Levie, K.,Schwarz, J.B.
Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators (PAMs): Tuning Deactivation Kinetics via Structure-Based Design.
J.Med.Chem., 59:2760-2779, 2016

PubMed Abstract: The N-methyl-D-aspartate receptor (NMDAR) is a Na(+) and Ca(2+) 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.

PubMed: 26919761
DOI: 10.1021/acs.jmedchem.5b02010

実験手法

X-RAY DIFFRACTION (2.12 Å)