Optimization of a Small Tropomyosin-Related Kinase B (TrkB) Agonist 7,8-Dihydroxyflavone Active in Mouse Models of Depression
Open accessAbstract
Structure-activity relationship study shows that the catechol group in 7,8-dihdyroxyflavone, a selective small TrkB receptor agonist, is critical for agonistic activity. To improve the poor pharmacokinetic profiles intrinsic to catechol-containing molecules and to elevate the agonistic effect of the lead compound, we initiated the lead optimization campaign by synthesizing various bioisosteric derivatives. Here we show that the optimized 2-methyl-8-(4'-(pyrrolidin-1-yl)phenyl)chromeno[7,8-d]imidazol-6(1H)-one derivative possesses enhanced TrkB stimulatory activity. Chronic oral administration of this compound significantly reduces the immobility in forced swim test and tail suspension test, two classical antidepressant behavioral animal models, which is accompanied by robust TrkB activation in hippocampus of mouse brain. Further, in vitro ADMET studies demonstrate that this compound possesses the improved features compared to the previous lead compound. Hence, this optimized compound may act as a promising lead candidate for in-depth drug development for treating various neurological disorders including depression.
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Bioisosteric 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. 2012
The Results report that bioisosteric compound 13 reduced immobility in both FST and TST at 2.5 mg/kg, while compound 11 was tested in FST at 5 mg/kg. The paper describes greater TrkB-stimulating potency for compound 13, but does not establish a more pronounced antidepressant effect than DHF or its derivatives in both behavioral tests. (LLM, conf=0.87)
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- Authors
- Liu, X., Chan, C.-B., Qi, Q., Xiao, G., Luo, H. R., He, X., & Ye, K.
- Affiliations
- Emory University (US)
- Centers for Disease Control and Prevention (US)
- Boston Children's Hospital (US)
- Northwestern University (US)
- Corresponding author
- Ye, Keqiang
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2012-10-03
- Volume
- 55
- Issue
- 19
- Pages
- 8524-8537
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC3491656
- OpenAlex
- W2080985284
- Cited by
- 60
- References
- 31
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 6 · 2021: 4 · 2020: 1 · 2019: 5 · 2018: 2 · 2017: 5 · 2016: 7 · 2015: 6 · 2014: 11 · 2013: 10
- FWCI
- 6.82
- 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 on Deafness and Other Communication Disorders (R01DC010204)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Pharmacology › Synthesis of Organic Compounds
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- 7,8-dihydroxyflavone, depression, structure-activity relationship, catechol groups, bioisosteres, pharmacokinetic optimization, antidepressant effects, forced swim test, tail suspension test, ADMET properties
- MeSH terms
- Animals, Antidepressive Agents, Brain, Depression, Humans, Imidazoles, Indoles, Male, Mice, Inbred C57BL, Motor Activity, Structure-Activity Relationship, Receptor, trkB, Flavanones, Mice, Neurogenesis, Hep G2 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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