Structural Modification And Structure-Activity Relationship Analysis Of PSD95-nNOS Uncoupler ZL006

Ischemic stroke is a common disease of serious harm to human health and life safety.When the occurrence of ischemic stroke,N-methyl-D-aspartate receptor(NMDAR)was activated,forming Tri-Complex with postsynaptic density protein 95(PSD95)and neuronal nitric oxide synthase(nNOS),resulting in a large release of NO molecules,thereby damaging nerve cells.Research shows that:the specific blocking coupling between PSD-95 protein and nNOS,can not affect the physiological function of the NMDAR and nNOS and reduce the release of NO.This has good security to reduce apoptosis and injury of neuronal after cerebral ischemic stroke and trauma,.Therefore,PSD95/nNOS unco-upling agent is expected to become a neuroprotective drugswith new mechanisms of action.In order to find PSD95/nNOS uncoupler highly active,this paper carried out the following aspects of work:1 The total of 25 target compounds were synthesized,and all target compounds were identified by 1H NMR.Studied to replace ZL006 hydrophilic hydroxyl to amino and carboxyl,different sizes groups of hydrophobic end and introduction of hydrophobic groups influence on the pharmacological activity of matrix.All target compounds have not been reported in the literature.2 The neuroprotective effect of partial synthesized target compounds were evaluated on nerve cells by the lactate dehydrogenase(Lactate dehydrogenase,LDH)determination method and structure-activity relationship was analyzed.Two target compounds(Zl,Z8)exhibit their protective effects on neuronal cells of 10 ?mol level.Three target compounds(Z2,Z14.Z20)exhibit their protective effects on neuronal cells of 1 ?mol level.The compound Z25 has good activity of 0.1 ?mol level.Therefore,according to the Z25 compound as the lead compound,the new high effective and low toxic neuroprotective drugs were developed by structure modification.3 According to the evaluation results of pharmacological activity,the structure-activity relationship analysed:On the hydrophilic end amino,carboxyl replace hydroxy,can keep the pharmacological activity;there is a close relationship between size of hydrophobic substituents and pharmacological activity;hydrophobic groups introduced link group has little influence on the pharmacological activity.