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.A...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.展开更多
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).
文摘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.
