Structural basis of subtype-selective competitive antagonism for GluN2C/2D-containing NMDA receptors

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 () and Hiro Furukawa ()
Additional contact information
Jue Xiang Wang: Cold Spring Harbor Laboratory
Mark W. Irvine: University of Bristol
Erica S. Burnell: University of Bristol
Kiran Sapkota: University of Nebraska Medical Center
Robert J. Thatcher: University of Bristol
Minjun Li: Cold Spring Harbor Laboratory
Noriko Simorowski: Cold Spring Harbor Laboratory
Arturas Volianskis: Queen Mary University of London
Graham L. Collingridge: University of Bristol
Daniel T. Monaghan: University of Nebraska Medical Center
David E. Jane: University of Bristol
Hiro Furukawa: Cold Spring Harbor Laboratory

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-14321-0

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