Design, Synthesis And Pharmacological Activity Evaluation Of PSD-95/nNOS Uncoupler ZL006 Analogue

Ischemic stroke remains a leading cause of death and disability worldwide.Numerous studies have shown that excessive amounts of NO which can mediate tissue injury are generated due to the following NMDA receptor/PSD95/nNOS pathway.PSD-95 mediates the coupling of nNOS to NMD A receptors in the central nervous system.NMDAR/PSD95/nNOS signaling pathway mediated the pathological release of NO.Due to the important physiological functions of NMDAR and nNOS,serious side effects will be produced wich can not be anticipated after inhibited NMDA or nNOS directly.To disrupting the couple of nNOS and PSD-95 would neither dislocate the physiological functions of NMDARs nor interfere with the nNOS activity and other subtype functions of NOS.Moreover these will also reduce the release of NO,and play a neuroprotective effect,thereby reducing neuronal apoptosis in ischemic stroke and injury.Previous studies have shown that the combination of the PSD-95 and nNOS increased signifincantly after NMDAR was over-activated,which mainly resulted from the over-activated nNOS.In the coupling process of nNOS and PSD-95,the spatial structure of nNOS has been changed.The inhibitor compounds(such as ZL006)can block the coupling of PSD-95 and nNOS.Uncoupling agents could reduce the combination of nNOS and PSD-95 to inhibit the excessive activation of nNOS and then reduce the releasing of NO,to achieve a neuroprotective effect.According to leading compound ZL006,22 novel compounds have been designed and synthesized which may be used as neuroprotection agents that disrupt PSD-95/nNOS interaction.The structures of these compunds have been confirmed by 1H NMR?13C NMR?IR?MS.The bioassays of some compounds have been done.The results of activity test suggested that some of them have strong activity which can disrupt PSD-95/nNOS pathway.