ABSTRACT
OBJECTIVE The N-methyl-D-aspartate(NMDA)receptor has been shown to be strongly associ-ated with rapid antidepressant effects.GW043 is a com-pound with a novel structure that we designed and syn-thesized to act on the NMDA receptor(NMDAR).METH-ODS In this study,we first confirmed the target of GW043 using a receptor binding assay.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 investi-gated the antidepressant effect of GW043 in rodent behavioral models such as FST,TST and CUMS.Fur-thermore,we explored the mechanism of GW043 onset using Western blotting,BrdU staining,Golgi staining and electrophysiological techniques.RESULTS GW043 interacts with high affinity only at the NMDAR.Electro-physiological studies have indicated that GW043 is a par-tial agonist of NMDAR.Meanwhile,behavioral experi-ments 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 new-born neurons to cause antidepressant effects.GW043,a partial agonist of NMDAR,reversed depression-like behav-ior in rats by modulating synaptic plasticity,suggesting an antidepressant effect.CONCLUSION The results suggest that GW043 is a partial agonist of NMDA recep-tors and has significant antidepressant effects.