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

IF 3.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Medicinal Chemistry Research Pub Date : 2026-03-26 DOI:10.1007/s00044-026-03542-5

Chunyu Wu, Shasha Yue, Benqin Tang, Jianbo Sun

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引用次数: 0

Abstract

Fifteen novel regulators targeting 5-HT_2AR 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_2AR 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-HT_2AR and SERT. Further study showed that the antidepressant mechanism of I₁₅ was associated with the downregulation of both 5-HT_2AR and SERT. In general, I₁₅ could be a potential antidepressant candidate for further study.

The alternative text for this image may have been generated using AI.

Abstract Image

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阿啡衍生物通过调节SERT和5-HT2AR改善抗抑郁活性的发现。

设计并合成了15种靶向5-HT2AR和血清素转运体（SERT）的新型调节因子，并对其抗抑郁活性进行了评价。阿啡类生物碱及其衍生物具有潜在的抗抑郁活性。将具有5-HT2AR拮抗作用的片段和有机硝酸盐NO供体引入到aporphine支架中。在所有目标化合物中，I15对皮质酮诱导的PC12细胞损伤的保护作用最好。体外细胞增殖试验表明，大多数化合物对神经元细胞无毒。此外，I15显著改善了小鼠的抑郁样行为。分子对接表明I15能够占据5-HT2AR和SERT的活性空腔。进一步研究表明，I15的抗抑郁机制与5-HT2AR和SERT的下调有关。总的来说，I15可能是一种潜在的抗抑郁药物，有待进一步研究。此图像的替代文本可能是使用AI生成的。

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来源期刊

Medicinal Chemistry Research 医学-医药化学

CiteScore

4.70

自引率

3.80%

发文量

162

审稿时长

5.0 months

期刊介绍： Medicinal Chemistry Research (MCRE) publishes papers on a wide range of topics, favoring research with significant, new, and up-to-date information. Although the journal has a demanding peer review process, MCRE still boasts rapid publication, due in part, to the length of the submissions. The journal publishes significant research on various topics, many of which emphasize the structure-activity relationships of molecular biology.