title: A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine Emory University School of Medicine, Room 141 Whitehead Building, 615 Michael Street, Atlanta, Georgia 30322, United States.
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.forename: Chi-Bun
authors.initials: CB
authors.lastname: Chan
authors.forename: Sung-Wuk
authors.initials: SW
authors.lastname: Jang
authors.forename: Sompol
authors.initials: S
authors.lastname: Pradoldej
authors.forename: Junjian
authors.initials: J
authors.lastname: Huang
authors.forename: Kunyan
authors.initials: K
authors.lastname: He
authors.forename: Lien H
authors.initials: LH
authors.lastname: Phun
authors.forename: Stefan
authors.initials: S
authors.lastname: France
authors.forename: Ge
authors.initials: G
authors.lastname: Xiao
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Jia
authors.forename: Hongbo R
authors.initials: HR
authors.lastname: Luo
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D047309:Flavones / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000187:drug effects*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: C485383:6,7-dihydroxyflavone; D000928:Antidepressive Agents; D047309:Flavones