5TP9

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

Summary for 5TP9

• Entry DOI: 10.2210/pdb5tp9/pdb
• Related: 5TPA
• Descriptor: Glutamate receptor ionotropic, NMDA 2A, Glutamate receptor ionotropic, NMDA 1, ACETATE ION, ... (8 entities in total)
• Functional Keywords: nmda receptor, glutamate, glycine, calcium channel, membrane, transport protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane; Multi-pass membrane protein: Q12879 Q05586
• Total number of polymer chains: 2
• Total formula weight: 66033.64

Authors

Wallweber, H.J.A.,Lupardus, P.J. (deposition date: 2016-10-20, release date: 2016-11-30, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.4 Å)