5I2K

Structure of the human GluN1/GluN2A LBD in complex with 7-{[ethyl(4-fluorophenyl)amino]methyl}-N,2-dimethyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-3-carboxamide (compound 19)

Summary for 5I2K

• Entry DOI: 10.2210/pdb5i2k/pdb
• Related: 5I2J 5I2N
• Descriptor: Glutamate receptor ionotropic, NMDA 2A, Glutamate receptor ionotropic, NMDA 1, GLUTAMIC ACID, ... (6 entities in total)
• Functional Keywords: glun1, glun2a, receptor, nmda, 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: 65889.14

Authors

Wallweber, H.J.A.,Lupardus, P.J. (deposition date: 2016-02-09, release date: 2016-03-16, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.86 Å)