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Author Notes:

To whom all correspondence should be addressed (kye@emory.edu) Tel: 404-712-2814

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Research Funding:

This work is supported by grants from National Institute of Health RO1 NS045627 to K. Ye.

Keywords:

  • TrkB agonist
  • BDNF
  • synthetic derivatives
  • antidepressant
  • neurogenesis

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

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Journal Title:

Journal of Medicinal Chemistry

Volume:

Volume 53, Number 23

Publisher:

, Pages 8274-8286

Type of Work:

Article | Post-print: After Peer Review

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 the lead. This novel compound also exhibits a more robust and longer TrkB activation effect in animals. Consequently, this new compound reveals more potent anti-apoptotic 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.

Copyright information:

© 2010 American Chemical Society

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