Tropoflavin

Tropoflavin, also known as 7,8-dihydroxyflavone, is a naturally occurring flavone found in Godmania aesculifolia, Tridax procumbens, and primula tree leaves.[2][3][4] It has been found to act as a potent and selective small-molecule agonist of the tropomyosin receptor kinase B (TrkB) (Kd ≈ 320 nM), the main signaling receptor of the neurotrophin brain-derived neurotrophic factor (BDNF).[5][6][7] Tropoflavin is both orally bioavailable and able to penetrate the blood–brain barrier.[8][9] A prodrug of tropoflavin with greatly improved potency and pharmacokinetics, R13 (and, formerly, R7), is under development for the treatment of Alzheimer's disease.[10][11]

Tropoflavin
Clinical data
Other names7,8-Dihydroxyflavone
Pharmacokinetic data
Bioavailability~5% (in mice)[1]
Elimination half-life< 30 minutes (in mice)[1]
Identifiers
IUPAC name
  • 7,8-Dihydroxy-2-phenyl-4H-chromen-4-one
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard100.048.903
Chemical and physical data
FormulaC15H10O4
Molar mass254.241 g·mol−1
3D model (JSmol)
SMILES
  • c1ccc(cc1)c2cc(=O)c3ccc(c(c3o2)O)O
InChI
  • InChI=1S/C15H10O4/c16-11-7-6-10-12(17)8-13(19-15(10)14(11)18)9-4-2-1-3-5-9/h1-8,16,18H
  • Key:COCYGNDCWFKTMF-UHFFFAOYSA-N

Tropoflavin has demonstrated therapeutic efficacy in animal models of a variety of central nervous system disorders,[7] including depression,[8] Alzheimer's disease,[12][13][14] cognitive deficits in schizophrenia,[15] Parkinson's disease,[5] Huntington's disease,[16] amyotrophic lateral sclerosis,[17] traumatic brain injury,[18] cerebral ischemia,[19][20] fragile X syndrome,[21] and Rett syndrome.[22] Tropoflavin also shows efficacy in animal models of age-associated cognitive impairment[23] and enhances memory consolidation and emotional learning in healthy rodents.[24][25] In addition, tropoflavin possesses powerful antioxidant activity independent of its actions on the TrkB receptor,[26] and protects against glutamate-induced excitotoxicity,[27] 6-hydroxydopamine-induced dopaminergic neurotoxicity,[28] and oxidative stress-induced genotoxicity.[29] It was also found to block methamphetamine-induced dopaminergic neurotoxicity, an effect which, in contrast to the preceding, was found to be TrkB-dependent.[30]

In 2017, evidence was published suggesting that tropoflavin and various other reported small-molecule TrkB agonists might not actually be direct agonists of the TrkB and might be mediating their observed effects by other means.[31][32]

Tropoflavin has been found to act as a weak aromatase inhibitor in vitro (Ki = 10 μM),[33] though there is evidence to suggest that this might not be the case in vivo.[5] In addition, it has been found to inhibit aldehyde dehydrogenase and estrogen sulfotransferase in vitro (Ki = 35 μM and 1–3 μM, respectively), though similarly to the case of aromatase, these activities have not yet been confirmed in vivo.[5] Unlike many other flavonoids, tropoflavin does not show any inhibitory activity on 17β-hydroxysteroid dehydrogenase.[34] Tropoflavin has also been observed to possess in vitro antiestrogenic effects at very high concentrations (Ki = 50 μM).[35][36]

A variety of close structural analogues of tropoflavin have also been found to act as TrkB agonists in vitro, including diosmetin (5,7,3'-trihydroxy-4'-methoxyflavone), norwogonin (5,7,8-trihydroxyflavone), eutropoflavin (4'-dimethylamino-7,8-dihydroxyflavone), 7,8,3'-trihydroxyflavone, 7,3'-dihydroxyflavone, 7,8,2'-trihydroxyflavone, 3,7,8,2'-tetrahydroxyflavone, and 3,7-dihydroxyflavone.[37] The highly hydroxylated analogue gossypetin (3,5,7,8,3',4'-hexahydroxyflavone), conversely, appears to be an antagonist of TrkB in vitro.[37]

Tropoflavin was also found to decrease mouse sleep in dark phase and reduce hypothalamus level of orexin A but not orexin B in mice.[38]

See also

References
  1. US application 20150274692, Keqiang Ye, "7,8-Dihydoxyflavone and 7,8-substituted flavone derivatives, compositions, and methods related thereto", published 2015-10-01, assigned to Emory University
  2. Andero R, Ressler KJ (July 2012). "Fear extinction and BDNF: translating animal models of PTSD to the clinic". Genes, Brain and Behavior. 11 (5): 503–12. doi:10.1111/j.1601-183X.2012.00801.x. PMC 3389160. PMID 22530815.
  3. Colombo PS, Flamini G, Christodoulou MS, Rodondi G, Vitalini S, Passarella D, Fico G (February 2014). "Farinose alpine Primula species: phytochemical and morphological investigations". Phytochemistry. 98: 151–9. doi:10.1016/j.phytochem.2013.11.018. hdl:2434/233766. PMID 24345641.
  4. Cell Press (2015). "Molecule found in tree leaves helps female mice combat weight gain; males unaffected". ScienceDaily. Retrieved 2015-03-19.
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  8. Liu X, Chan CB, Jang SW, Pradoldej S, Huang J, He K, Phun LH, France S, Xiao G, Jia Y, Luo HR, Ye K (2010). "A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect". J. Med. Chem. 53 (23): 8274–86. doi:10.1021/jm101206p. PMC 3150605. PMID 21073191.
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