摘要
A series of pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione derivatives was designed and synthesized,and their neuroprotective activity against SH-SY5Y cell injury induced by N-methyl-D-aspartic acid(NMDA)was evaluated.All the compounds showed significant neuroprotective effects,especially B16,which showed excellent performance and better activity than the positive control ifenprodil(B16:56.2%±0.6%;ifenprodil:41.0%±2.7%).Further investigation indicated that B16 could attenuate the Ca^(2+)influx induced by NMDA in SH-SY5Y cells and Western blotting also showed that B16 could attenuate the NR2B upregulation in SH-SY5Y cells induced by NMDA.The molecular docking results showed that compound B16 fitted in the binding pocket of NR2B-NMDAR well and could interact with binding sites of compounds 1 and 2 simultaneously.The ADME/Tox prediction results suggested that compound B16 had good blood-brain barrier(BBB)permeability and the zero alert of Pan Assay Interference Structures(PAINS)indicated that B16 could not elicit false-positive activities.These results strongly suggest that B16 is a promising and effective candidate neuroprotective compound,and that NR2B-NMDAR is a potential target of B16.
基金
This work was supported by the National Natural Science Foundation of China(No.21977074)
the Science and Technology Projects from the Educational Department of Liaoning Province,China(No.2019LQN02).
