Objective：The aimofthestudywasto explore the structure-activity relationship of PSD95-nNOS decoupling agent ZL006 (1)，and the mechanism of decoupling. Methods：Basedon the PSD95-nNOS protein-protein interaction inhibitor ZL006 reported by our group，four series of 21 novel ZL006 derivatives were designed andsynthesized by modifying its lipophilic part，linker and Salicylic acid structure. All the structures were confirmed by 1 H NMR，13C NMR and ESI-MS. The protective effect of the target compounds on glutamate-induced damage of human neuroblastoma cells(SH-SY5Y)was tested by LDH experiment，and the cytotoxicity of the target compounds was tested by CCK-8 staining. Results：Most of the compounds had protective activity against cells，among which compounds 5e and 27a were comparable to the neuroprotective activity of the positive control compound ZL006(51.24%，48.42% at 10 μmol/L)，and compound 23 showed better cytoprotective activity than ZL006(54.34% at 10 μmol/L，29.58% at 1 μmol/L)and showed lower cytotoxicity(2.85% at 25 μmol/L). Conclusion：This study not only enriches the diversity of chemical structures suitable for PSD95-nNOS protein-protein interaction but also provides a useful tool to further explore the neuroprotection therapeutic potential.