The N-methyl-D-aspartate (NMDA) receptor family regulates various CNS functions such as synaptic plasticity;however, hypo or hyper-activation of NMDA receptors (NMDARs) is critically involved in many neurological and psychiatric conditions. To date, most therapeutic efforts have focused on inhibitors of NMDA receptor activity. However, there are other clinical indications for which an NMDA receptor potentiator is more likely to be appropriate. Presently, there are no preclinical studies of positive allosteric modulators for NMDA receptors. Recently, the joint laboratories of the two PIs discovered a family of compounds that are positive allosteric modulators (PAMs) as well as negative allosteric modulators (NAMs) of NMDARs. These agents have novel sites of action, novel mechanisms of action, and several novel patterns of activity. Their members include the first general NMDAR PAMs, and PAMs that are selective for each of the four GluN1/GluN2 subtypes. NMDAR PAMs have important therapeutic applications, such as for treating schizophrenia or enhancing cognition. Thus, these agents represent significant opportunities as neurobiological tools and are unique lead compounds for developing agents that can modulate NMDAR activity and synaptic plasticity for therapeutic benefit. Further progress in this critical field requires a muc better understanding of the mechanism of action and how that is related to pharmacological activity and receptor modulation. We propose that NMDAR PAMs act at two closely related sites to modulate receptor deactivation and desensitization. Experiments will identify these mechanisms of action of the NMDA receptor PAMs and characterize the respective pharmacophores responsible for these actions. Our goal is to resolve these relationships to provide firm ground for further drug development.

Public Health Relevance

Many neuropathological conditions such as epilepsy, stroke, pain, schizophrenia, drug addition, depression, and cell death in various neurodegenerative diseases are mediated by either the over- or under-activation of the NMDA family of L-glutamate neurotransmitter receptors. The goal of this project is to develop novel compounds that selectively modulate the function of discrete subtypes of NMDA receptors. These will help determine disease mechanisms and generate new therapeutic agents for neurological diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH060252-09A1
Application #
8506867
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Driscoll, Jamie
Project Start
2001-04-06
Project End
2018-01-31
Budget Start
2013-04-01
Budget End
2014-01-31
Support Year
9
Fiscal Year
2013
Total Cost
$391,176
Indirect Cost
$83,224
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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
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
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
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
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
Volianskis, Arturas; Bannister, Neil; Collett, Valerie J et al. (2013) Different NMDA receptor subtypes mediate induction of long-term potentiation and two forms of short-term potentiation at CA1 synapses in rat hippocampus in vitro. J Physiol 591:955-72
Costa, Blaise Mathias; Irvine, Mark W; Fang, Guangyu et al. (2012) Structure-activity relationships for allosteric NMDA receptor inhibitors based on 2-naphthoic acid. Neuropharmacology 62:1730-6
Irvine, Mark W; Costa, Blaise M; Dlaboga, Daniel et al. (2012) Piperazine-2,3-dicarboxylic acid derivatives as dual antagonists of NMDA and GluK1-containing kainate receptors. J Med Chem 55:327-41

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