Synthesis And Biological Activity Of NNOS PDZ Domain Inhibitor

Anxiety disorder is obvious mental depression caused by dysfunction,it is a common disease wicth has serious hazards to health and life quality.In the preliminary work,we found and confirmed a new target for the treatment of anxiety,namely uncoupling nNOS-Capon interaction has anxiolytic effect.Throu-gh analyzing the structure characteristic of nNOS PDZ binding site domain,N-(2-carboxylacetyl)-D-valine methyl ester(CL-2)was designed and synthesized for uncoupling of nNOS-Capon,showing potent anxiolytic activity.We designed and synthesized 28 target compounds on the basis of compound CL-2 and the characteristics of the PDZ domain.We took the inspects into consideration which had influence on the activity of CL-2,including the distance between the two carboxyl groups,alkyl groups,the carbonyl groups directly connected with N-side chain,carboxyl equivalents and the application of chemical drug delivery systems in compounds.We took anxiolytic activity tests in mice with MY-6?MY-8?MY-10?MY-11.In the elevated plus maze test,the compound MY-8 could significantly increase the time of mice in open arm compared with the control group.In the open field test,it could increased the movement distance of mice in the central area.These tests showed that MY-8 had obvious anxiolytic effects.MY-6,MY-10,MY-11 in the elevated plus maze,open field and novelty-suppressed feeding experiments did not show anxiolytic activity.