Design,Synthesis And Antidepressant Activity Of New NMDA Receptor Modulators

More and more people are oppressed with the rapid development of economy and society,and the changes of living environment.The prevalence of depression attracts concern all over the world.According to the report of the World Health Organization in 2001,depression will be the second disease by 2020.However,clinical trials showed that more than half of patients did not respond to first-line antidepressants,and the patients who received the treatment needed to wait to 2-4 weeks of treatment before getting benefit.Many factors,such as monoamine deficiency,heredity and environment,hypothalamus-pituitary-adrenal(HPA)axis dysfunction and neurogenesis may explain the pathophysiology of depression.The combination and interaction of these factors are related to the pathogenesis of depression,but no hypothesis can explain all the symptoms.From the discovery of imipramine in 1951 to the discovery of Prozac in 1972,it took too long.Recently,antidepressants have made a lot of progress.For example,Zulresso and S-ketamine were marketed in the United States in March this year.Ketamine,an N-methyl-D-aspartic acid(NMDA)receptor(NMDAR)antagonist,can work rapidly,sustain antidepressant effects in patients for a week and reduce the risk of suicide,but ketamine is a narcotic with addiction which limits its development.The NMDA system has emerged as a highlight for novel drug discovery of depression,and the NMDA receptor modulators may decrease depressive symptoms quickly and effectively.This dissertation contains three chapters.Chapter 1,the depression hypothesis and antidepressant drugs,and many reseach progresses of antidepression have been summerized.Neural plasticity hypothesis and NMDA receptor with NMDAR-based antidepressant canditates are the main parts of the discussion.According to the structure of GLYX-13,NYX-2925,NRX-1074 and D-serine,isobutyryl and hydroxymethyl ware introduced to L-proline.The tetra-atomic ring was opened and substituents were introduced to the targets.Chapter 2 describes the experimental details,25 compounds were synthesized via the addition of different groups on L-proline.All the compounds were confinned by HRMS,1H-NMR,13C NMR and IR spectras.The third chapter is the activity test.Biological activities of the synthesized compounds were tested and the antidepressant activities of compounds zcy-12,zcy-14,zcy-24 and zcy-25 were evaluated by tail suspension test(TST)in mice,and the results showed that the four compounds had no significant antidepressant effect,which would provide a basis for future research.