The Study Of Proline Analogs Targeting NMDA Receptors In The Treatment Of Depression

Depression is a chronic,recurrent and life-threatening illness that affects up to 800 million people globally and places a huge burden on individuals and society.On the basis of the current treatment of depression,conventional antidepressant drugs affecting the monoamine system are unsatisfactory,and innovative antidepressant drugs are still needed.Treatment for the next generation of depression needs to be more effective,faster,and better tolerated than currently applied antidepressants.From current preclinical and clinical data,it is known that the ketamine,an antagonist of the NMDA receptor,has a good effect on the treatment of depression,a fast speed and a long effect.However,ketamine cannot be considered as a novel antidepressant because of its side effects and abuse potential.There is an urgent need for an anti-depressant drug based on a novel mechanism to overcome the above disadvantages.NRX-1074 is a partial agonist of the NMDA receptor glycine binding site,which is orally active and a second-generation compound of GLYX-13.It has similar pharmacological properties to the first generation and both have good drug resistance.Sex,speed of action,long duration of effects,etc.,but the efficacy of NRX-1074 is much stronger.NRX-1074 is a peptide analogue,which has a large polarity,poor lipophilicity,and poor ability to penetrate biological membranes.Therefore,this subject has attempted to modify the structure of NRX-1074 with hydrophobic groups for certain polar groups.Substitutions are made to increase the lipid solubility of the molecule in order to enhance the oral activity and central distribution of the compound.At the same time,some polar fragments of NRX-1074 were removed,the molecular weight was reduced,the drug-making properties were improved,and the effect of these polar fragments on the activity was examined.In this dissertation,NRX-1074 was used as the lead compound.After replacing the acyl moiety by ring-closing,a total of 27 novel compounds in two series were synthesized.All the synthesized compounds were confirmed by HRMS,1H-NMR,13C-NMR and IR.In the activity test section,mice were used to test the antidepressant effects of LYB 1-0 and LYB 1-Boc of the test articles in order to obtain lead compounds for the treatment of new depressive disorder drugs,providing the basis for further optimization in the future.