9MUM

Crystal structure of GluN1/GluN2A ligand-binding domain in complex with Compound 11, Glycine and Glutamate

This is a non-PDB format compatible entry.

Summary for 9MUM

• Entry DOI: 10.2210/pdb9mum/pdb
• Descriptor: Glutamate receptor ionotropic, NMDA 1, Glutamate receptor ionotropic, NMDA 2A, GLYCINE, ... (6 entities in total)
• Functional Keywords: nmdars, lbd, ion channels, metal transport, negative modulator, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 69369.29

Authors

Shaffer, P.L.,Duda, D.M. (deposition date: 2025-01-14, release date: 2025-03-05, Last modification date: 2025-03-12)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.97 Å)