A novel NMDA receptor modulator: the antidepressant effect and mechanism of GW043

Background and Purpose: The N-methyl-D-aspartate (NMDA) receptor has been shown to be strongly associated with rapid antidepressant effects. GW043 is a compound with a novel structure that we designed and synthesized to act on the NMDA receptor (NMDAR). In this study, we first confirmed the target of GW043 using a receptor binding assay. Experimental Approach: We observed the effect of GW043 on NMDAR currents in vivo and in vitro assays using a membrane clamp technique with a view to characterizing the function of GW043. We investigated the antidepressant effect of GW043 in rodent behavioral models such as FST, TST and CUMS. Furthermore, we explored the mechanism of GW043 onset using western blot, BrdU staining, Golgi staining and electrophysiological techniques. Key Results: GW043 interacts with high affinity (IC50=0.143 nM) only at the NMDAR. Electrophysiological studies have indicated that GW043 is a partial agonist of NMDAR. Meanwhile, behavioral experiments were conducted to confirm the antidepressant effect of GW043 in rodents. The mechanism study found that GW043 regulate synaptic plasticity through LTP and BDNF-mTOR pathways and increase the number of newborn neurons to cause antidepressant effects. Conclusion and Implications: GW043, a partial agonist of NMDAR, reversed depression-like behavior in rats by modulating synaptic plasticity, suggesting an antidepressant effect.