A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect
Open accessAbstract
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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DHF was first described as an antioxidant and later identified as a TrkB agonist after screening of flavone derivatives.
“It was first described as an antioxidant and later identified as a TrkB agonist after a screening of flavone derivatives (Choi et al. 2010, Liu et al. 2010).”
From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as Liu et al. 2010
The Results (Structure-activity relationship study; page unavailable) identify 7,8-DHF as a TrkB agonist and report testing numerous flavonoid derivatives for TrkB activity. The Discussion (page unavailable) describes flavonoids generally as antioxidants, but does not say that 7,8-DHF was first described as an antioxidant or that the derivative screening was how it was initially identified as a TrkB agonist. (LLM, conf=0.87)
Experimental — accuracy not yet measuredBioisosteric derivatives of DHF show an even more pronounced antidepressant effect in the FST and TST, requiring a lower dose for a more potent effect.
“Liu et al. optimized the molecule by synthesizing various bioisosteric derivatives and showed an even more pronounced antidepressant effect in both the FST and TST requiring a lower dose for a more potent effect (Liu et al. 2010; Liu et al. 2012).”
From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as Liu et al. 2010
The Discussion reports that 4′-DMA-7,8-DHF had a more potent antidepressant effect than 7,8-DHF at 1 mg/kg, while the two had comparable effects at 5 mg/kg in wild-type mice. The Results and Experimental Section describe a forced swim test (FST), but our copy does not report a tail suspension test (TST); it therefore does not support the claim about both tests. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSmall molecules directly targeting TrkB signaling have shown promising antidepressant-like results in preclinical studies.
“These molecules have shown promising antidepressant-like results in preclinical studies (Liu et al., 2010, 2012b).”
From BDNF - a key transducer of antidepressant effects (2016) · cites this paper as Liu et al., 2010
DHF increases neurogenesis in the hippocampus of naïve mice.
“and to increase neurogenesis in the hippocampus of naïve mice (Liu et al. 2010).”
From Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression (2018) · cites this paper as Liu et al. 2010
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- Authors
- Liu, X., Chan, C.-B., Jang, S.-W., Pradoldej, S., Huang, J., He, K., Phun, L. H., France, S., Xiao, G., Jia, Y., Luo, H. R., & Ye, K.
- Affiliations
- Emory University (US)
- Department of Pathology and Laboratory Medicine Emory University School of Medicine, Room 141 Whitehead Building, 615 Michael Street, Atlanta, Georgia 30322, United States
- Georgia Institute of Technology (US)
- Centers for Disease Control and Prevention (US)
- Boston Children's Hospital (US)
- Corresponding author
- Ye, Keqiang
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2010-11-12
- Volume
- 53
- Issue
- 23
- Pages
- 8274-8286
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC3150605
- OpenAlex
- W2142181595
- Cited by
- 208
- References
- 41
- Citations by year
- 2026: 11 · 2025: 7 · 2024: 7 · 2023: 12 · 2022: 14 · 2021: 23 · 2020: 15 · 2019: 12 · 2018: 13 · 2017: 12 · 2016: 16 · 2015: 17 · 2014: 15 · 2013: 20 · 2012: 9
- FWCI
- 7.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS045627)
- Topics
- Health Sciences › Medicine › Pharmacology › Synthesis of Organic Compounds
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Pharmacology › Flavonoids in Medical Research
- Keywords
- 7,8-dihydroxyflavone, TrkB agonist, tropomyosin receptor kinase B, antidepressant effects, neurogenesis, dentate gyrus, structure-activity relationship, anti-apoptotic effects, oral bioavailability, flavone derivatives
- MeSH terms
- Animals, Antidepressive Agents, Male, Mice, Inbred C57BL, Magnetic Resonance Spectroscopy, Structure-Activity Relationship, Apoptosis, Spectrometry, Mass, Electrospray Ionization, Flavones, Mice, Neurogenesis
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