Correlation Engine 2.0
Clear Search sequence regions

Sizes of these terms reflect their relevance to your search.

N-Methyl-D-aspartate receptors (NMDARs) play critical roles in the central nervous system. Their heterotetrameric composition generates subtypes with distinct functional properties and spatio-temporal distribution in the brain, raising the possibility for subtype-specific targeting by pharmacological means for treatment of neurological diseases. While specific compounds for GluN2A and GluN2B-containing NMDARs are well established, those that target GluN2C and GluN2D are currently underdeveloped with low potency and uncharacterized binding modes. Here, using electrophysiology and X-ray crystallography, we show that UBP791 ((2S*,3R*)-1-(7-(2-carboxyethyl)phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid) inhibits GluN2C/2D with 40-fold selectivity over GluN2A-containing receptors, and that a methionine and a lysine residue in the ligand binding pocket (GluN2D-Met763/Lys766, GluN2C-Met736/Lys739) are the critical molecular elements for the subtype-specific binding. These findings led to development of UBP1700 ((2S*,3R*)-1-(7-(2-carboxyvinyl)phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid) which shows over 50-fold GluN2C/2D-selectivity over GluN2A with potencies in the low nanomolar range. Our study shows that the L-glutamate binding site can be targeted for GluN2C/2D-specific inhibition.


Jue Xiang Wang, Mark W Irvine, Erica S Burnell, Kiran Sapkota, Robert J Thatcher, Minjun Li, Noriko Simorowski, Arturas Volianskis, Graham L Collingridge, Daniel T Monaghan, David E Jane, Hiro Furukawa. Structural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors. Nature communications. 2020 Jan 22;11(1):423

Expand section icon Mesh Tags

Expand section icon Substances

PMID: 31969570

View Full Text