NMDAR/TRPM4-IN-2 free base (compound 8) is a potent NMDAR/TRPM4 interaction interface inhibitor. NMDAR/TRPM4-IN-2 free base shows neuroprotective activity. NMDAR/TRPM4-IN-2 free base prevents NMDA-induced cell death and mitochondrial dysfunction in hippocampal neurons, with an IC50 of 2.1 μM. NMDAR/TRPM4-IN-2 free base protects mice from MCAO-induced brain damage and NMDA-induced retinal ganglion cell loss.In Vitro: NMDAR/TRPM4-IN-2 free base (compound 8) (0-10 μM) reduces the interactions of GluN2A and GluN2B with TRPM4 in a dose-dependent manner.
NMDAR/TRPM4-IN-2 free base eliminates the CREB shutoff pathway and restores ERK1/2 activation and IEG induction while sparing the synaptic activity-driven, transcription-promoting activities of NMDARs.