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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Driscoll, Jamie
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University of Nebraska Medical Center
Schools of Medicine
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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
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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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