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<p>Fifteen novel regulators targeting 5-HT<sub>2A</sub>R and serotonin transporter (SERT) were designed and synthesized, and their antidepressant activities were evaluated. Aporphine alkaloids and their derivatives have potential antidepressant activity. Fragments exhibiting 5-HT<sub>2A</sub>R antagonism and organic nitrate NO donors were introduced into the aporphine scaffold. Among all the target compounds, <b>I</b><sub><b>15</b></sub> was screened with the best protective effect against corticosterone-induced PC12 cell injury. In vitro cell proliferation assays showed that most compounds were nontoxic to neuronal cells. In addition, <b>I</b><sub><b>15</b></sub> significantly ameliorated the depression-like behavior of mice. Molecular docking indicated that <b>I</b><sub><b>15</b></sub> was able to occupy the active cavity of 5-HT<sub>2A</sub>R and SERT. Further study showed that the antidepressant mechanism of <b>I</b><sub><b>15</b></sub> was associated with the downregulation of both 5-HT<sub>2A</sub>R and SERT. In general, <b>I</b><sub><b>15</b></sub> could be a potential antidepressant candidate for further study.</p><p></p>

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Discovery of aporphine derivatives with improved antidepressant activity by regulating SERT and 5-HT2AR.

  • 期刊论文

  • 发表日期：

    2026年3月26日

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  • Chunyu Wu,
  • Shasha Yue,
  • Benqin Tang,
  • Jianbo Sun

摘要

Fifteen novel regulators targeting 5-HT2AR and serotonin transporter (SERT) were designed and synthesized, and their antidepressant activities were evaluated. Aporphine alkaloids and their derivatives have potential antidepressant activity. Fragments exhibiting 5-HT2AR antagonism and organic nitrate NO donors were introduced into the aporphine scaffold. Among all the target compounds, I15 was screened with the best protective effect against corticosterone-induced PC12 cell injury. In vitro cell proliferation assays showed that most compounds were nontoxic to neuronal cells. In addition, I15 significantly ameliorated the depression-like behavior of mice. Molecular docking indicated that I15 was able to occupy the active cavity of 5-HT2AR and SERT. Further study showed that the antidepressant mechanism of I15 was associated with the downregulation of both 5-HT2AR and SERT. In general, I15 could be a potential antidepressant candidate for further study.