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.
Highlights
N-Methyl-D-aspartate receptors (NMDARs) play critical roles in the central nervous system
Each receptor subunit has a modular build with an amino-terminal domain (ATD), a ligand-binding domain (LBD), a transmembrane domain (TMD), and a carboxyl-terminal domain (CTD) (Fig. 1a, b)
Previously obtained structures of isolated ATDs and LBDs11–13 are identical to the ones observed in the intact NMDARs9,10 demonstrating the physiological relevance of conducting structural biology on the isolated extracellular domains
Summary
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. NMDARs play critical roles in brain development and functions such as learning and memory and have been implicated in an array of neurological diseases and disorders, including depression, stroke, seizure, schizophrenia, Alzheimer’s disease and Parkinson’s disease[1,2] Their roles have been most extensively studied as part of the postsynaptic density where NMDARs co-localize with non-NMDAR iGluRs including α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptors (AMPARs) along with many other postsynaptic density proteins. Screening efforts led to the discovery of those similar compounds, UBP141 and UBP145, with up to approximately tenfold GluN2C/2D selectivity[28]
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