In vitro activity: QNZ46 is a novel non-competitive and NR2C/NR2D-selective NMDA receptor antagonist with IC50 values of 3, 6, 229, and>300,>300 μM for NR2D, NR2C, NR2A, NR2B, and GluR1, respectively. NMDA receptors are ionotropic glutamate receptors that mediate excitatory synaptic transmission and have been implicated in several neurological diseases. QNZ46 inhibits NMDA receptor function in a noncompetitive and voltage-independent manner by an unconventional mechanism that requires binding of glutamate to the GluN2 subunit, but not glycine binding to the GluN1 subunit. Evaluation of the structural determinants responsible for the subunit-selectivity of QNZ46 revealed that these compounds act at a new site that has not previously been described. Residues residing in the part of the agonist binding domain immediately adjacent to the transmembrane helices appear to control selectivity of QNZ46 for GluN2C- and GluN2D-containing receptors. These residues are well-positioned to sense glutamate binding to GluN2 and thus to mediate glutamate-dependent actions.

Kinase Assay: QNZ46 is a noncompetitive inhibitor of GluN2C/D containing NMDA receptors. KD and IC50 values for binding and inhibition of GluN1/Glun2D receptors by QNZ46 are 4.9 and 3.9 μM, respectively. QNZ46 does not compete for binding of glutamate or glycine, but QNZ46 receptor binding requires the binding of glutamate to the GluN2 subunit.

Cell Assay: