Design,synthesis and antidepressant activity of novel genipin derivatives
The pathogenesis of depression is complex,and some existing monoamine antidepressants have problems such as drug resistance or off-target failure.Traditional Chinese medicine has the characteristics of"multi-component and multi-target",and has been used in the treatment of depression in clinical practice.Yueju pill is effective in the treatment of depression.Geniposide and ligustrazine,the active ingredients of Gardeniae fructus and Ligusticum sinense'Chuanxiong',play a key role in the treatment of depression.In this study,based on the neuroprotective activity of genipin and the rapid antidepressant activity of tetramethylpyrazine,a series of novel genipin derivatives were designed and synthesized through pharmacophore assembly principle,and their neuroprotective activity and antidepressant effect were investigated.The results showed that the novel genipin derivatives had well neuroprotective activity on the glutamate-induced HT-22 cell model,with compounds W-1 and W-3 showing better protective activity.In behavioral despair depression(BDD)model mice,compound W-3 was found to have better antidepressant activity than W-1 in tail suspension test and forced swimming test.Further study on the behavior of chronic unpredictable mild stress(CUMS)model mice showed that W-3 could significantly improve the depression-like behavior of model mice.All animal experiments were approved by the Experimental Animal Ethics Committee of Anhui University of Chinese Medicine(approval number:AHUCM-mouse-2022027).The effects of the preferred compound W-3 on protein kinase A(PKA),cAMP response element binding protein(CREB),brain-derived neurotrophic factor(BDNF),5-hydroxytryptamine 1A(5-HT1A)receptor,N-methyl-D-aspartate ionic glutamate receptor 2A(GluN2A)and N-methyl-D-aspartate ionic glutamate receptor 2B(GluN2B)were analyzed by Western blot.W-3 treatment significantly up-regulated the protein expression of PKA,CREB,BDNF and 5-HT1A,and down-regulated the protein expression of GluN2A and GluN2B.The results of qRT-PCR were consistent with those of Western blot.According to the above results,compound W-3 has a potential antidepressant effect,and its mechanism may be related to the activation of PKA-CREB-BDNF signaling pathway by regulating the expression of GluN2A,GluN2B and 5-HT1A receptor proteins.
novel genipin derivativedrug designantidepressant activitymechanism of action
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