9MUL

Crystal structure of GluN1/GluN2A ligand-binding domain in complex with Compound 1, Glycine and Glutamate

これはPDB形式変換不可エントリーです。

9MUL の概要

• エントリーDOI: 10.2210/pdb9mul/pdb
• 分子名称: Glutamate receptor ionotropic, NMDA 1, Glutamate receptor ionotropic, NMDA 2A, GLYCINE, ... (6 entities in total)
• 機能のキーワード: nmdars, lbd, ion channels, metal transport, negative modulator, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 69370.35

構造登録者

Shaffer, P.L.,Duda, D.M. (登録日: 2025-01-14, 公開日: 2025-03-05, 最終更新日: 2025-03-12)

主引用文献

Bischoff, F.P.,Van Brandt, S.,Viellevoye, M.,De Cleyn, M.,Surkyn, M.,Carbajo, R.J.,Dominguez Blanco, M.,Wroblowski, B.,Karpowich, N.K.,Steele, R.A.,Schalk-Hihi, C.,Miller, R.,Duda, D.,Shaffer, P.,Ballentine, S.,Simavorian, S.,Lord, B.,Neff, R.A.,Bonaventure, P.,Gijsen, H.J.M.
Design, Synthesis, and Characterization of GluN2A Negative Allosteric Modulators Suitable for In Vivo Exploration.
J.Med.Chem., 68:4672-4693, 2025

PubMed Abstract: -Methyl-d-aspartate receptors are ionotropic glutamate receptors that mediate fast excitatory neurotransmission in the central nervous system. These receptors play essential roles in synaptic plasticity, learning, and memory and are implicated in various neuropathological and psychiatric disorders. Selective modulation of NMDAR subtypes, particularly GluN2A, has proven challenging. The derivatives and are potent and selective for GluN2A receptors, yet their physical properties limit their in vivo utility. In this study, we optimized the / scaffold by modifying the linker region between the distal halogenated aromatic ring and the central pyrazine nucleus, resulting in the identification of potent and selective compounds with improved drug-like properties. Notably, compound was used to develop the first GluN2A NAM-based radioligand, and compound showed improved pharmacokinetics and dose-dependent receptor occupancy in vivo. Thus, we provide an array of powerful new tools for the study of GluN2A receptors.

PubMed: 39960408
DOI: 10.1021/acs.jmedchem.4c02751

実験手法

X-RAY DIFFRACTION (2.4 Å)