Structural Basis of NR2B-Selective Antagonist Recognition by N-Methyl-d-aspartate Receptors
Abstract
N-Methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors endowed with unique pharmacological and functional properties. In particular, their high permeability to calcium ions confers on NMDARs a central role in triggering long term changes in synaptic strength. Under excitotoxic pathological conditions, such as those occurring during brain trauma, stroke, or Parkinson’s or Huntington’s diseases, calcium influx through NMDAR channels can also lead to neuronal injury. This argues for the use of NMDAR antagonists as potential therapeutic agents. To date, the most promising NMDAR antagonists are ifenprodil and derivatives, compounds that act as noncompetitive inhibitors selective for NMDARs containing the NR2B subunit. Recent studies have identified the large N-terminal domain (NTD) of NR2B as the region controlling ifenprodil sensitivity of NMDARs. We present here a detailed characterization of the ifenprodil binding site using both experimental and computational approaches. 3D homology modeling reveals that ifenprodil fits well in a closed cleft conformation of the NRB NTD; however, ifenprodil can adopt either of two possible binding orientations of opposite direction. By studying the effects of cleft mutations, we show that only the orientation in which the phenyl moiety points deep toward the NTD hinge is functionally relevant. Moreover, based on our model, we identify novel NTD NR2B residues that are crucial for conferring ifenprodil sensitivity and provide functional evidence that these residues directly interact with the ifenprodil molecule. This work provides a general insight into the origin of the subunit-selectivity of NMDAR noncompetitive antagonists and offer clues for the discovery of novel NR2B-selective antagonists.
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BibTeX
@article{mony2026structural,
title = {{Structural Basis of NR2B-Selective Antagonist Recognition by N-Methyl-d-aspartate Receptors}},
author = {Laetitia Mony and Lucie Krzaczkowski and Manuel Leonetti and Anne Le Goff and Karine Alarcon and Jacques Neyton and Hughes-Olivier Bertrand and Francine Acher and Pierre Paoletti},
journal = {Molecular Pharmacology},
year = {2026},
month = oct,
doi = {10.1124/mol.108.050971},
url = {https://hal.science/hal-05773251v1},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Structural Basis of NR2B-Selective Antagonist Recognition by N-Methyl-d-aspartate Receptors
AU - Laetitia Mony
AU - Lucie Krzaczkowski
AU - Manuel Leonetti
AU - Anne Le Goff
AU - Karine Alarcon
AU - Jacques Neyton
AU - Hughes-Olivier Bertrand
AU - Francine Acher
AU - Pierre Paoletti
PY - 2026
DA - 2026/10/01
JO - Molecular Pharmacology
DO - 10.1124/mol.108.050971
UR - https://hal.science/hal-05773251v1
AB - N-Methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors endowed with unique pharmacological and functional properties. In particular, their high permeability to calcium ions confers on NMDARs a central role in triggering long term changes in synaptic strength. Under excitotoxic pathological conditions, such as those occurring during brain trauma, stroke, or Parkinson’s or Huntington’s diseases, calcium influx through NMDAR channels can also lead to neuronal injury. This argues for the use of NMDAR antagonists as potential therapeutic agents. To date, the most promising NMDAR antagonists are ifenprodil and derivatives, compounds that act as noncompetitive inhibitors selective for NMDARs containing the NR2B subunit. Recent studies have identified the large N-terminal domain (NTD) of NR2B as the region controlling ifenprodil sensitivity of NMDARs. We present here a detailed characterization of the ifenprodil binding site using both experimental and computational approaches. 3D homology modeling reveals that ifenprodil fits well in a closed cleft conformation of the NRB NTD; however, ifenprodil can adopt either of two possible binding orientations of opposite direction. By studying the effects of cleft mutations, we show that only the orientation in which the phenyl moiety points deep toward the NTD hinge is functionally relevant. Moreover, based on our model, we identify novel NTD NR2B residues that are crucial for conferring ifenprodil sensitivity and provide functional evidence that these residues directly interact with the ifenprodil molecule. This work provides a general insight into the origin of the subunit-selectivity of NMDAR noncompetitive antagonists and offer clues for the discovery of novel NR2B-selective antagonists.
SN - 0026-895X
ER -