Design,Synthesis And Evaluation Of Antidepressant Activity Of Novel NMDA Receptor Glycine Binding Site Antagonists

Depression is a disease with high incidence,high suicide rates and a wide range of effects worldwide.In recent years,there have been many important findings in the study of antidepressant drugs,such as several advances in NMDA receptor drugs: Johnson &Johnson’s S-ketamine therapy for major depression was approved for marketing,and AV-101 was approved by FDA as a fast-track treatment for major depression.But the antidepressant effects of these drugs are slow to take effect,usually after a few weeks,and are difficult to treat in patients with suicidal thoughts.And a significant proportion(about a third)of patients on existing drugs do not respond.There are also many side effects from existing drugs.There is an urgent need for effective and safe antidepressants for refractory depression.Targeting NMDA receptors may lead to better solutions.Ketamine,an NMDA receptor blocker,ACTS quickly and significant relief from depression can be observed a few hours after intravenous administration.But ketamine is a drug with significant hallucinogenic addictive side effects,which limits its use.Some agonists at the glycine site of NMDA receptor,Gly-13 and NYX-2925,showed significant antidepressant effects in animal models without ketamine like side effects.Unfortunately,the failure of Gly-13 phase III clinical trial indicated that this mechanism may be unreliable.So we turned our attention to the mechanism of AV-101,which blocks the glycine binding site of NMDA receptor.AV-101 has shown antidepressant efficacy in early clinical trials,with no ketamine like side effects,and may become a new treatment for depression.Therefore,a series of possible NMDA receptor glycine site antagonists were designed and synthesized,and their antidepressant activity was evaluated.This topic is divided into three chapters,the first chapter mainly reviews the harm of depression,the pathogenesis,and the drug research direction of depression,and according to the NMDA receptor glycine site antagonist RPR-104632 as the basic skeleton modification,so that the molecules can easily pass through the blood-brain barrier,modify the carboxyl fragments,carboxyl groups replaced by carbonyl groups,sulfonyl groups replaced by acyl groups,these can reduce polarity,while the molecules are easy to pass through the blood-brain barrier to consider molecular weight,the previous changes are also molecular weight reduction changes.In chapter 2,a total of31 compounds were synthesized by modified molecules,which were determined as target compounds.chapter 3 is to select three compounds from the synthesizedcompounds,which are J-1、J-10、J-11 as the activity evaluation compounds of the mouse tail suspension experiment.each compound was gavage in the mice with three levels of high and low concentration respectively.reference to the control experiment,the antidepressant activity of the compounds was evaluated by the resting time of the mice.the results show that all three compounds have no antidepressant activity and provide a reference for future related research.