FIGURE 2.

Targetted pharmacological inhibition of extrasynaptic NMDARs. Preferential targetting of extrasynaptic NMDARs is a strategy to inhibit downstream toxic events (including mitochondrial dysfunction, activation of death signalling cascades, CREB dephosphorylation and shut-off, and structural damage), whilst sparing protective mechanisms associated with synaptic NMDAR activity [such as CREB activation and expression of neuroprotective immediate early genes (IEG)]. Memantine shows a preferential inhibitory effect of extrasynaptic NMDARs, which has been harnessed and developed with the NitroMemantine drug series. Selective NR2B inhibitors aim to take advantage of preferential NR2B association within extrasynaptic NMDAR heterotetramers. NDMAR-TRPM4 (N/T) interface inhibitors target the death-promoting complex formed between NMDAR and TRPM4 which, due to the absence of TRPM4 in synapses, mediate the neurodegenerative effects of extrasynaptic NMDAR activation.