The Design, Synthesis And Structure-activity Relationship Of PSD95-nNOS Uncoupling Agent

neuropathic pain are caused by peripheral and central nervous system lesions or damage,common type of neuropathic pain includ diabetes neuralgia,trigeminal neuralgia after herpes zoster neuralgia,neuralgia,and various injury after spinal cord injury,inflammation or residual neuralgia after surgery.The common characteristic of these diseases is that their pathogenesis is still not very clear,and clinical routine analgesia treatments are poor effects.NMDAR-PSD-95-nNOS is a new target for the treatment of cerebral apoplexy and pain.PSD95-nNOS uncoupling agent,are able to block the NMDAR-nNOS specific signaling pathways,with no effect to the normal physiological function of NMDAR and nNOS.and it can reduce the NO release at the same time,so as to reduce the injury and apoptosis of neuronal cell and produce analgesic effect.In this paper,based on previous studies,we have been clear about the ZL006structure-activity relationship,and ZL006 as the lead compounds,we modified its structure as follows:1,change the 5-position of ZL006,with different alkyl group,discusses its analgesic activity;2,replaced the hydropxyl group with amino groups in the hydrophilic moiety.3,considering ZL006 hydrophilic large,go against through the blood brain barrier,so will the hydrophilic end-COOH and-OH the esterification and amidation.Through this modification above,it is hope to improve activity of these compounds by changing the lipo-hydro partition coefficient.26 target compounds have been designed and synthesized.The pharmacological experiment result showed that seven compounds have analgesic effect in neuropathicpain,and obviously better than the ZL006,which has further improved the structure-activity relationship of PSD95-nNOS uncoupling agent,and provided a direction and reference for future research.