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Published on: September 23, 2015
Discovery of aporphine derivatives with improved antidepressant activity by regulating SERT and 5-HT2AR
Chunyu Wu1, Shasha Yue1, Benqin Tang2
1State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China.
Abstract:
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.
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