Designing dual-target inhibitors targeting 5-HT2AR and MAO-A could synergistically promote interstitial 5-HT levels, so as to exhibit a more efficient antidepressant effect. On the premise of maintaining the original pharmacophore binding, arylpiperazine scaffolds and 5-oxygen-substituted oxoisoaporphines were hybridized to afford 15 dual-target inhibitors through suitable linkers. Among all inhibitors, I 14 exhibited the best inhibitory activities against 5-HT2AR and MAO-A. In vitro cell proliferation assays showed that most compounds were nontoxic to neuronal cells and normal hepatocytes. I 14 also significantly ameliorated the depression-like behavior of zebrafish and mice. Further study revealed that I 14 was able to occupy the active cavity of 5-HT2AR and MAO-A with multiple hydrogen bonding forces and π–π stacking interaction. I 14 was also able to repair the damage of mice hippocampal neuronal cells and reduce the expression of 5-HT2AR in mice brain tissue. In conclusion, I 14 could be a potential antidepressant candidate for further study.
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