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

摘要: N-Methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate that mediate excitatory synaptic transmission and have been implicated in numerous neurological disorders. NMDARs typically comprise two GluN1 GluN2 subunits. The four subtypes (GluN2A-GluN2D) distinct functional properties gene expression patterns, which contribute to diverse roles for the brain. Here, we present a series of GluN2C/2D-selective negative allosteric modulators built around N-aryl benzamide (NAB) core. prototypical compound, NAB-14, is >800-fold selective recombinant GluN2C/GluN2D over GluN2A/GluN2B Xenopus oocytes has an IC50 value 580 nM at GluN2D-containing expressed mammalian cells. NAB-14 inhibits triheteromeric (GluN1/GluN2A/GluN2C) with modestly reduced potency efficacy compared diheteromeric (GluN1/GluN2C/GluN2C) receptors. Site-directed mutagenesis suggests structural determinants inhibition...