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 #
5R01MH060252-10
Application #
8641718
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
2014-02-01
Budget End
2015-01-31
Support Year
10
Fiscal Year
2014
Total Cost
$321,774
Indirect Cost
$52,177
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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
Collingridge, Graham L; Volianskis, Arturas; Bannister, Neil et al. (2013) The NMDA receptor as a target for cognitive enhancement. Neuropharmacology 64:13-26
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; Volianskis, Arturas et al. (2012) Coumarin-3-carboxylic acid derivatives as potentiators and inhibitors of recombinant and native N-methyl-D-aspartate receptors. Neurochem Int 61:593-600
Monaghan, Daniel T; Irvine, Mark W; Costa, Blaise Mathias et al. (2012) Pharmacological modulation of NMDA receptor activity and the advent of negative and positive allosteric modulators. Neurochem Int 61:581-92
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
Jullienne, Amandine; Montagne, Axel; Orset, Cyrille et al. (2011) Selective inhibition of GluN2D-containing N-methyl-D-aspartate receptors prevents tissue plasminogen activator-promoted neurotoxicity both in vitro and in vivo. Mol Neurodegener 6:68
Costa, Blaise Mathias; Irvine, Mark W; Fang, Guangyu et al. (2010) A novel family of negative and positive allosteric modulators of NMDA receptors. J Pharmacol Exp Ther 335:614-21
Suarez, F; Zhao, Q; Monaghan, D T et al. (2010) Functional heterogeneity of NMDA receptors in rat substantia nigra pars compacta and reticulata neurones. Eur J Neurosci 32:359-67
Costa, Blaise Mathias; Feng, Bihua; Tsintsadze, Timur S et al. (2009) N-methyl-D-aspartate (NMDA) receptor NR2 subunit selectivity of a series of novel piperazine-2,3-dicarboxylate derivatives: preferential blockade of extrasynaptic NMDA receptors in the rat hippocampal CA3-CA1 synapse. J Pharmacol Exp Ther 331:618-26

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