NMDA receptors are critically involved in a variety of CMS functions such as learning, pain amplification, motor pattern generation, and experience-dependent synapse formation and elimination. These receptors are also involved in various neuropathological conditions such as epilepsy, opiate addiction, and neuronal cell death following head/spinal cord injury, sroke, AIDS infection, and possibly the pathophysiology in schizophrenia, Alzheimer's, Parkinson's, and Huntingon's. However, in the absence of selective pharmacological tools, relatively little is known about the role of different NMDA receptor subtypes in these critical cellular processes and disease states. While most of the functional and pharmacological heterogeneity is due to the four genetically-distinct NR2 NMDA receptor subunits, highly-selective antagonists are only available for the NR2B subuit. Over the past few years we have generated a novel series of compounds that are the only NR2C, and NR2D agents known and have already revealed differential roles for NMDA receptor subtypes in synaptic physiology and plasticity. However, it has proven difficult to develop highly-selective agents because the central glutamate binding site is highly conserved for each of the NR2 subunits (as well as for the various AMPA and kainate receptor glutamate binding sites). We have now identified the subunit-specific structural features of the NR2 glutamate binding sites and we propose a two-step approach to developing NR2D and NR2C subtype-selective antagonists. 1) Use a combination of molecular modeling and site-directed mutagenesis of recombinant receptors tested in Xenopus oocytes to define the precise placement of a select group of NMDA antagonists that are large enough to reach the subunit-specific amino acid residues at the edge of the glutamate-binding pocket. 2) Using this structural information, design and test antagonists that are predicted to interact with amino acid residues that are specific to NR2D and other NR2 subunits. Using this approach, we have already designed several antagonists that are predicted by molecular modeling techniques to be highly-selective for NR2D subunit-containing NMDA receptors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH060252-08
Application #
7817069
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Winsky, Lois M
Project Start
2001-04-06
Project End
2012-06-30
Budget Start
2010-04-01
Budget End
2012-06-30
Support Year
8
Fiscal Year
2010
Total Cost
$269,874
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
France, Grace; Fernández-Fernández, Diego; Burnell, Erica S et al. (2017) Multiple roles of GluN2B-containing NMDA receptors in synaptic plasticity in juvenile hippocampus. Neuropharmacology 112:76-83
Sapkota, Kiran; Irvine, Mark W; Fang, Guangyu et al. (2017) Mechanism and properties of positive allosteric modulation of N-methyl-d-aspartate receptors by 6-alkyl 2-naphthoic acid derivatives. Neuropharmacology 125:64-79
Chopra, Divyan A; Sapkota, Kiran; Irvine, Mark W et al. (2017) A single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors. Sci Rep 7:6933
Sapkota, Kiran; Mao, Zhihao; Synowicki, Paul et al. (2016) GluN2D N-Methyl-d-Aspartate Receptor Subunit Contribution to the Stimulation of Brain Activity and Gamma Oscillations by Ketamine: Implications for Schizophrenia. J Pharmacol Exp Ther 356:702-11
Wallis, James L; Irvine, Mark W; Jane, David E et al. (2015) An interchangeable role for kainate and metabotropic glutamate receptors in the induction of rat hippocampal mossy fiber long-term potentiation in vivo. Hippocampus 25:1407-17
Chopra, Divyan A; Monaghan, Daniel T; Dravid, Shashank M (2015) Bidirectional Effect of Pregnenolone Sulfate on GluN1/GluN2A N-Methyl-D-Aspartate Receptor Gating Depending on Extracellular Calcium and Intracellular Milieu. Mol Pharmacol 88:650-9
Irvine, Mark W; Fang, Guangyu; Eaves, Richard et al. (2015) Synthesis of a Series of Novel 3,9-Disubstituted Phenanthrenes as Analogues of Known NMDA Receptor Allosteric Modulators. Synthesis (Stuttg) 47:1593-1610
Volianskis, Arturas; France, Grace; Jensen, Morten S et al. (2015) Long-term potentiation and the role of N-methyl-D-aspartate receptors. Brain Res 1621:5-16
Collingridge, Graham L; Volianskis, Arturas; Bannister, Neil et al. (2013) The NMDA receptor as a target for cognitive enhancement. Neuropharmacology 64:13-26
Gautam, Vivek; Trinidad, Jonathan C; Rimerman, Ronald A et al. (2013) Nedd4 is a specific E3 ubiquitin ligase for the NMDA receptor subunit GluN2D. Neuropharmacology 74:96-107

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