Designing dual-target inhibitors targeting 5-HT_2AR 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, I₁₄ exhibited the best inhibitory activities against 5-HT_2AR and MAO-A. In vitro cell proliferation assays showed that most compounds were nontoxic to neuronal cells and normal hepatocytes. I₁₄ also significantly ameliorated the depression-like behavior of zebrafish and mice. Further study revealed that I₁₄ was able to occupy the active cavity of 5-HT_2AR and MAO-A with multiple hydrogen bonding forces and π–π stacking interaction. I₁₄ was also able to repair the damage of mice hippocampal neuronal cells and reduce the expression of 5-HT_2AR in mice brain tissue. In conclusion, I₁₄ could be a potential antidepressant candidate for further study.

中文翻译：

---

开发具有改善抗抑郁活性的 MAO-A 和 5-HT2AR 双抑制剂

_{设计靶向 5-HT 2A} R 和 MAO-A的双靶点抑制剂可以协同促进间质 5-HT 水平，从而表现出更有效的抗抑郁作用。在保持原有药效团结合的前提下，芳基哌嗪支架与5-氧取代的氧代异吗啡肽通过合适的接头杂交得到15种双靶点抑制剂。在所有抑制剂中，I ₁₄对5-HT _2A R 和MAO-A 的抑制活性最好。体外细胞增殖试验表明，大多数化合物对神经元细胞和正常肝细胞无毒。I ₁₄还显着改善了斑马鱼和小鼠的抑郁样行为。进一步的研究表明，I ₁₄能够占据5-HT _2A R 和MAO-A 的活性空腔，具有多种氢键合力和π-π 堆积相互作用。I ₁₄还能够修复小鼠海马神经元细胞的损伤，降低小鼠脑组织中5-HT _{2AR的表达。}总之，I ₁₄可能是进一步研究的潜在抗抑郁药候选者。