一种合成的 7,8-二羟基黄酮衍生物可促进神经发生，并表现出很强的抗抑郁作用。
A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect.
机构信息
Department of Pathology and Laboratory Medicine Emory University School of Medicine, Room 141 Whitehead Building, 615 Michael Street, Atlanta, Georgia 30322, United States.
出版信息
J Med Chem. 2010 Dec 9;53(23):8274-86. doi: 10.1021/jm101206p. Epub 2010 Nov 12.
Abstract
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.
摘要
7,8-二羟基黄酮是一种最近被鉴定出的小分子原肌球蛋白受体激酶 B（TrkB）激动剂。我们的初步结构-活性关系（SAR）研究表明，7,8-二羟基是激动作用所必需的。为了提高先导化合物的激动活性，我们进行了广泛的 SAR 研究并合成了许多衍生物。我们成功地鉴定出了 4'-二甲氨基-7,8-二羟基黄酮，其显示出比先导更高的 TrkB 激动活性。这种新型化合物在动物中还表现出更强和更持久的 TrkB 激活作用。因此，这种新化合物显示出更强的抗凋亡活性。有趣的是，4'-二甲氨基-7,8-二羟基黄酮及其先导的慢性口服给药强烈促进了齿状回中的神经发生，并表现出明显的抗抑郁作用。因此，我们的数据支持合成的 4'-二甲氨基-7,8-二羟基黄酮及其先导均为口服生物利用的 TrkB 激动剂，并具有很强的抗抑郁作用。
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