A Novel Negative Allosteric Modulator Selective for GluN2C/2D-Containing NMDA Receptors Inhibits Synaptic Transmission in Hippocampal Interneurons.

N-Methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors that mediate excitatory synaptic transmission and have been implicated in numerous neurological disorders. NMDARs typically comprise two GluN1 and two GluN2 subunits. The four GluN2 subtypes (GluN2A-GluN2D) have distinct functional properties and gene expression patterns, which contribute to diverse functional roles for NMDARs in the brain. Here, we present a series of GluN2C/2D-selective negative allosteric modulators built around a N-aryl benzamide (NAB) core. The prototypical compound, NAB-14, is >800-fold selective for recombinant GluN2C/GluN2D over GluN2A/GluN2B in Xenopus oocytes and has an IC50 value of 580 nM at recombinant GluN2D-containing receptors expressed in mammalian cells. NAB-14 inhibits triheteromeric (GluN1/GluN2A/GluN2C) NMDARs with modestly reduced potency and efficacy compared to diheteromeric (GluN1/GluN2C/GluN2C) receptors. Site-directed mutagenesis suggests that structural determinants for NAB-14 inhibition reside in the GluN2D M1 transmembrane helix. NAB-14 inhibits GluN2D-mediated synaptic currents in rat subthalamic neurons and mouse hippocampal interneurons, but has no effect on synaptic transmission in hippocampal pyramidal neurons, which do not express GluN2C or GluN2D. This series possesses some druglike physical properties and modest brain permeability in rat and mouse. Altogether, this work identifies a new series of negative allosteric modulators that are valuable tools for studying GluN2C- and GluN2D-containing NMDAR function in brain circuits, and suggests that the series has the potential to be developed into therapies for selectively modulating brain circuits involving the GluN2C and GluN2D subunits.

Design, synthesis, and structure-activity relationship of a novel series of GluN2C-selective potentiators.

NMDA receptors are tetrameric complexes composed of GluN1 and GluN2A-D subunits that mediate a slow Ca(2+)-permeable component of excitatory synaptic transmission. NMDA receptors have been implicated in a wide range of neurological diseases and thus represent an important therapeutic target. We herein describe a novel series of pyrrolidinones that selectively potentiate only NMDA receptors that contain the GluN2C subunit. The most active analogues tested were over 100-fold selective for recombinant GluN2C-containing receptors over GluN2A/B/D-containing NMDA receptors as well as AMPA and kainate receptors. This series represents the first class of allosteric potentiators that are selective for diheteromeric GluN2C-containing NMDA receptors.

Novel NMDA receptor modulators: an update.

INTRODUCTION: The NMDA receptor is a ligand-gated ion channel that plays a critical role in higher level brain processes and has been implicated in a range of neurological and psychiatric conditions. Although initial studies for the use of NMDA receptor antagonists in neuroprotection were unsuccessful, more recently, NMDA receptor antagonists have shown clinical promise in other indications such as Alzheimer's disease, Parkinson's disease, pain and depression. Based on the clinical observations and more recent insights into receptor pharmacology, new modulatory approaches are beginning to emerge, with potential therapeutic benefit. AREAS COVERED: The article covers the known pharmacology and important features regarding NMDA receptors and their function. A discussion of pre-clinical and clinical relevance is included, as well. The subsequent patent literature review highlights the current state of the art targeting the receptor since the last review in 2010. EXPERT OPINION: The complex nature of the NMDA receptor structure and function is becoming better understood. As knowledge about this receptor increases, it opens up new opportunities for targeting the receptor for many therapeutic indications. New strategies and advances in older technologies will need to be further developed before clinical success can be achieved. First-in-class potentiators and subunit-selective agents form the basis for most new strategies, complemented by efforts to limit off-target liability and fine-tune on-target properties.