New Anti-stroke Drug Discovery Based On ZL006 Metabolism Study In Vivo

Stroke is the second biggest leading cause of death and disability worldwide which has been a serious killer to human health.It is lack of effective clinical treatment due to the complexity of the pathogenesis.Postsynaptic density protein-95(PSD-95)is a key scaffolding protein that links neuronal nitric oxide synthase(nNOS)with the N-methyl-D-aspartic acid receptor(NMDAR),and mediates a specific coupling between NMDAR activati on and NO production in the central nervous system(CNS).As a signaling m acromolecular,the NMDAR/PSD-95/nNOS complex has been implicated in sev eral neurological disorders including chronic pain2,ischemic brain injury3,depr ession4 and Parkinson's disease5.In recent years,the NMDAR/PSD-95/nNOS c omplex has emerged as a promising target for treating these CNS disorders;so me peptide fragments and small-molecule inhibitors have achieved the disruptio n of the NMDAR/PSD-95/nNOS interaction.2-4 Among these,4-((3,5-dichloro-2-hydroxybenzyl)amino)-2-hydroxybenzoic acid(ZL006)attracted more considerab le attention,which selectively blocked the ischemia-induced PSD-95/nNOS cou pling,exhibited remarkable neuroprotective activity and ameliorated focal cerebr al ischemic damage,without effect on aggressive behavior and spatial memory.So far,ZL006 has served as a potential candidate for cerebral ischemia.However,the fast metabolism and low permeability across the blood brain barr ier(BBB)have restricted its further use for cerebral ischemia.In this manuscri pt,we designed cleverly six ZL006 analogs and carried out metabolic studies on these compounds,which identified the phenolic hydroxyl group of aromatic ring A was its major binding site with glucuronic acid.Moreover,compared with ZL006,the compounds that were esterified at carboxyl group of aromatic ring B were observed having significantly higher permeability acro ss BBB and longer duration time.