A Synthetic 7,8-Dihydroxyflavone Derivative Promotes Neurogenesis and Exhibits Potent Antidepressant Effect

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• 作者：Xia Liu ; Chi-Bun Chan ; Sung-Wuk Jang ; Sompol Pradoldej ; Junjian Huang ; Kunyan He ; Lien H. Phun ; Stefan France ; Ge Xiao ; Yonghui Jia ; Hongbo R. Luo ; Keqiang Ye
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：December 9, 2010
• 年：2010
• 卷：53
• 期：23
• 页码：8274-8286
• 全文大小：1244K
• 年卷期：v.53,no.23(December 9, 2010)
• ISSN：1520-4804

文摘

7,8-Dihydroxyflavone is a recently identified small molecular tropomyosin-receptor-kinase B (TrkB) agonist. Our preliminary structural−activity relationship (SAR) study showed that the 7,8-dihydroxy groups are essential for the agonistic effect. To improve the lead compound’s agonistic activity, we have conducted an extensive SAR study and synthesized numerous derivatives. We have successfully identified 4′-dimethylamino-7,8-dihydroxyflavone that displays higher TrkB agonistic activity than that of the lead. This novel compound also exhibits a more robust and longer TrkB activation effect in animals. Consequently, this new compound reveals more potent antiapoptotic activity. Interestingly, chronic oral administration of 4′-dimethylamino-7,8-dihydroxyflavone and its lead strongly promotes neurogenesis in dentate gyrus and demonstrates marked antidepressant effects. Hence, our data support that the synthetic 4′-dimethylamino-7,8-dihydroxyflavone and its lead both are orally bioavailable TrkB agonists and possess potent antidepressant effects.