Design, Synthesis And Activity Study Of Indole-based NNOS-Capon Uncoupling Agent

Anxiety,with the full name of anxiety neurosis,is a kind of autonomic nervous disorders which is manifested with repeated and continued anxiety,fear and other symptoms.Current anxiolytics have side effects,addiction and tolerance and other limitations.Therefore,it's of urgent need for us to find anti-anxiety drugs with new mechanism and minor side effects.Research shows that uncoupling nNOS-Capon interaction can block nNOS-Capon-Dexras1 ternary complex signaling pathways,then inhibit Dexras1 activity and improve the Erk activity,thus showing anxiolytic effects.Meanwhile,Capon can interact with MKK3,thereby activate kinases p38MAPK and lead to neuronal death.So neuroprotective effects will exhibit by inhibiting nNOS-Capon coupling between the blocking nNOS-Capon-MKK3 pathway.In this dissertation,we synthesized small non-peptide molecule compound based on the C-terminal tetrapeptide EIAV of Capon,which could combine to nNOS PDZ competitively and achieve anxiolytic and neuroprotective effects by blocking signaling pathways.We designed all of the target compounds by changing the indole ring side chain substitute.All compounds had been confirmed by MS,~1H NMR and some of them also had neuroprotective activity study.Our experimental results showed that the compound BLX-27 and BLX-30 had significant neuroprotective effects.However,relevant pharmacological activity is still under testing.