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

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† Department of Pathology and Laboratory Medicine Emory University School of Medicine, Room 141 Whitehead Building, 615 Michael Street, Atlanta, Georgia 30322, United States
‡ School of Chemistry and Biochemistry, Georgia Institute of Technology, 901 Atlantic Drive, NW, Atlanta, Georgia 30332-0400, United States
§ Centers for Disease Control and Prevention, 4770 Buford Highway, Atlanta, Georgia 30341, United States
∥ Department of Pathology and Lab Medicine, Harvard Medical School and Children's Hospital Boston, 10214 Karp Research Building, 1 Blackfan Circle, Boston, Massachusetts 02115, United States
*To whom correspondence should be addressed. Phone: 404-712-2814. E-mail: [email protected]
Cite this: J. Med. Chem. 2010, 53, 23, 8274–8286
Publication Date (Web):November 12, 2010
https://doi.org/10.1021/jm101206p
Copyright © 2010 American Chemical Society
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    Abstract

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    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.

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    CBC analysis of TrkB agonist-treated mice; structure−activity relationship study; 2,4′-DMA-7,8-DHF is more potent than 7,8-DHF in triggering TrkB activation in primary neurons; TrkB is activated by 7,8-DHF via oral administration in a dose dependent manner. histology exampination of drug-treated mice and control saline-treated mice; cell growth and cytotoxicity assays. This material is available free of charge via the Internet at http://pubs.acs.org.

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