5TP9

Structure of the human GluN1/GluN2A LBD in complex with compound 2 (GNE9178)

5TP9 の概要

• エントリーDOI: 10.2210/pdb5tp9/pdb
• 関連するPDBエントリー: 5TPA
• 分子名称: Glutamate receptor ionotropic, NMDA 2A, Glutamate receptor ionotropic, NMDA 1, ACETATE ION, ... (8 entities in total)
• 機能のキーワード: nmda receptor, glutamate, glycine, calcium channel, membrane, 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: 66033.64

構造登録者

Wallweber, H.J.A.,Lupardus, P.J. (登録日: 2016-10-20, 公開日: 2016-11-30, 最終更新日: 2024-10-16)

主引用文献

Villemure, E.,Volgraf, M.,Jiang, Y.,Wu, G.,Ly, C.Q.,Yuen, P.W.,Lu, A.,Luo, X.,Liu, M.,Zhang, S.,Lupardus, P.J.,Wallweber, H.J.,Liederer, B.M.,Deshmukh, G.,Plise, E.,Tay, S.,Wang, T.M.,Hanson, J.E.,Hackos, D.H.,Scearce-Levie, K.,Schwarz, J.B.,Sellers, B.D.
GluN2A-Selective Pyridopyrimidinone Series of NMDAR Positive Allosteric Modulators with an Improved in Vivo Profile.
ACS Med Chem Lett, 8:84-89, 2017

PubMed Abstract: The -methyl-d-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca and Na. NMDAR dysfunction is associated with numerous neurological and psychiatric disorders, including schizophrenia, depression, and Alzheimer's disease. Recently, we have disclosed GNE-0723 (), a GluN2A subunit-selective and brain-penetrant positive allosteric modulator (PAM) of NMDARs. This work highlights the discovery of a related pyridopyrimidinone core with distinct structure-activity relationships, despite the structural similarity to GNE-0723. GNE-5729 (), a pyridopyrimidinone-based NMDAR PAM, was identified with both an improved pharmacokinetic profile and increased selectivity against AMPARs. We also include X-ray structure analysis and modeling to propose hypotheses for the activity and selectivity differences.

PubMed: 28105280
DOI: 10.1021/acsmedchemlett.6b00388

実験手法

X-RAY DIFFRACTION (2.4 Å)