Tropoflavin

Overview

Tropoflavin, also known as 7,8-dihydroxyflavone (7,8-DHF), is a naturally occurring flavone found in Godmania aesculifolia, Tridax procumbens, and Primula vulgaris. 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). Tropoflavin is both orally bioavailable and able to penetrate the blood–brain barrier. A prodrug of tropoflavin with greatly improved potency and pharmacokinetics, R13 (and, formerly, R7), is under development for the treatment of Alzheimer's disease.[1–10] WP

Tropoflavin has demonstrated therapeutic efficacy in animal models of a variety of central nervous system disorders, including depression, Alzheimer's disease, cognitive deficits in schizophrenia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, cerebral ischemia, fragile X syndrome, and Rett syndrome. Tropoflavin also shows efficacy in animal models of age-associated cognitive impairment and enhances memory consolidation and emotional learning in healthy rodents. In addition, tropoflavin possesses powerful antioxidant activity independent of its actions on the TrkB receptor, and protects against glutamate-induced excitotoxicity, 6-hydroxydopamine-induced dopaminergic neurotoxicity, and oxidative stress-induced genotoxicity. It was also found to block methamphetamine-induced dopaminergic neurotoxicity, an effect which, in contrast to the preceding, was found to be TrkB-dependent.[4][6][7][11–29] WP

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.[30][31] WP

Tropoflavin has been found to act as a weak aromatase inhibitor in vitro (Kᵢ = 10 μM), though there is evidence to suggest that this might not be the case in vivo. In addition, it has been found to inhibit aldehyde dehydrogenase and estrogen sulfotransferase in vitro (Kᵢ = 35 μM and 1–3 μM, respectively), although similarly to the case of aromatase, these activities have not yet been confirmed in vivo. Unlike many other flavonoids, tropoflavin does not show any inhibitory activity on 17β-hydroxysteroid dehydrogenase. Tropoflavin has also been observed to possess in vitro antiestrogenic effects at very high concentrations (Kᵢ = 50 μM).[4][32–35] WP

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. The highly hydroxylated analogue gossypetin (3,5,7,8,3',4'-hexahydroxyflavone), conversely, appears to be an antagonist of TrkB in vitro.[7] WP

Tropoflavin was also found to decrease mouse sleep in dark phase and reduce hypothalamus level of orexin A, but not orexin B, in mice.[36] WP

Chemistry

Formula

C15H10O4 PC

CAS number

38183-03-8 PC

Molar mass (g/mol)

254.24 PC

IUPAC name (computed by PubChem)

7,8-dihydroxy-2-phenylchromen-4-one PC

SMILES

C1=CC=C(C=C1)C2=CC(=O)C3=C(O2)C(=C(C=C3)O)O PC

InChIKey

COCYGNDCWFKTMF-UHFFFAOYSA-N PC

PubChem CID

1880

IUPAC name

7,8-Dihydroxy-2-phenyl-4H-chromen-4-one WP

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Journal / agency Andero R, Ressler KJ. Fear extinction and BDNF: translating animal models of PTSD to the clinic. Genes, Brain and Behavior. July 2012. doi:10.1111/j.1601-183X.2012.00801.x · PMID 22530815 · PMC3389160
2. Journal / agency Colombo PS, Flamini G, Christodoulou MS, Rodondi G, Vitalini S, Passarella D, Fico G. Farinose alpine Primula species: phytochemical and morphological investigations. Phytochemistry. February 2014. doi:10.1016/j.phytochem.2013.11.018 · PMID 24345641
3. Other Cell Press. Molecule found in tree leaves helps female mice combat weight gain; males unaffected. 2015
4. Journal / agency Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y, Wilson WD, Xiao G, Blanchi B, Sun YE, Ye K. A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc. Natl. Acad. Sci. U.S.A. 2010. doi:10.1073/pnas.0913572107 · PMID 20133810 · PMC2823863
5. Journal / agency Liu X, Obianyo O, Chan CB, Huang J, Xue S, Yang JJ, Zeng F, Goodman M, Ye K. Biochemical and biophysical investigation of the brain-derived neurotrophic factor mimetic 7,8-dihydroxyflavone in the binding and activation of the TrkB receptor. J. Biol. Chem. 2014. doi:10.1074/jbc.M114.562561 · PMID 25143381 · PMC4183797
6. Journal / agency Zeng Y, Wang X, Wang Q, Liu S, Hu X, McClintock SM. Small molecules activating TrkB receptor for treating a variety of CNS disorders. CNS Neurol Disord Drug Targets. 2013. doi:10.2174/18715273113129990089 · PMID 23844685
7. Journal / agency Liu X, Chan CB, Jang SW, Pradoldej S, Huang J, He K, Phun LH, France S, Xiao G, Jia Y, Luo HR, Ye K. A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect. J. Med. Chem. 2010. doi:10.1021/jm101206p · PMID 21073191 · PMC3150605
8. Journal / agency Liu X, Chan CB, Qi Q, Xiao G, Luo HR, He X, Ye K. Optimization of a small tropomyosin-related kinase B (TrkB) agonist 7,8-dihydroxyflavone active in mouse models of depression. J. Med. Chem. 2012. doi:10.1021/jm301099x · PMID 22984948 · PMC3491656
9. Journal / agency Chen C, Wang Z, Zhang Z, Liu X, Kang SS, Zhang Y, Ye K. The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. January 2018. doi:10.1073/pnas.1718683115 · PMID 29295929 · PMC5777001
10. Journal / agency Liu C, Chan CB, Ye K. 7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders. Translational Neurodegeneration. 2016. doi:10.1186/s40035-015-0048-7 · PMID 26740873 · PMC4702337
11. Journal / agency Castello NA, Nguyen MH, Tran JD, Cheng D, Green KN, LaFerla FM. 7,8-Dihydroxyflavone, a small molecule TrkB agonist, improves spatial memory and increases thin spine density in a mouse model of Alzheimer disease-like neuronal loss. PLOS ONE. 2014. doi:10.1371/journal.pone.0091453 · PMID 24614170 · PMC3948846
12. Journal / agency Chen C, Li XH, Zhang S, Tu Y, Wang YM, Sun HT. 7,8-dihydroxyflavone ameliorates scopolamine-induced Alzheimer-like pathologic dysfunction. Rejuvenation Res. 2014. doi:10.1089/rej.2013.1519 · PMID 24325271
13. Journal / agency Zhang Z, Liu X, Schroeder JP, Chan CB, Song M, Yu SP, Weinshenker D, Ye K. 7,8-dihydroxyflavone prevents synaptic loss and memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology. 2014. doi:10.1038/npp.2013.243 · PMID 24022672 · PMC3895241
14. Journal / agency Yang YJ, Li YK, Wang W, Wan JG, Yu B, Wang MZ, Hu B. Small-molecule TrkB agonist 7,8-dihydroxyflavone reverses cognitive and synaptic plasticity deficits in a rat model of schizophrenia. Pharmacol. Biochem. Behav. 2014. doi:10.1016/j.pbb.2014.03.013 · PMID 24662915
15. Journal / agency Jiang M, Peng Q, Liu X, Jin J, Hou Z, Zhang J, Mori S, Ross CA, Ye K, Duan W. Small-molecule TrkB receptor agonists improve motor function and extend survival in a mouse model of Huntington's disease. Hum. Mol. Genet. 2013. doi:10.1093/hmg/ddt098 · PMID 23446639 · PMC3658168
16. Journal / agency Korkmaz OT, Aytan N, Carreras I, Choi JK, Kowall NW, Jenkins BG, Dedeoglu A. 7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosis. Neurosci. Lett. 2014. doi:10.1016/j.neulet.2014.02.058 · PMID 24637017 · PMC5906793
17. Journal / agency Wu CH, Hung TH, Chen CC, Ke CH, Lee CY, Wang PY, Chen SF. Post-injury treatment with 7,8-dihydroxyflavone, a TrkB receptor agonist, protects against experimental traumatic brain injury via PI3K/Akt signaling. PLOS ONE. 2014. doi:10.1371/journal.pone.0113397 · PMID 25415296 · PMC4240709
18. Journal / agency Wang B, Wu N, Liang F, Zhang S, Ni W, Cao Y, Xia D, Xi H. 7,8-dihydroxyflavone, a small-molecule tropomyosin-related kinase B (TrkB) agonist, attenuates cerebral ischemia and reperfusion injury in rats. J. Mol. Histol. 2014. doi:10.1007/s10735-013-9539-y · PMID 24045895
19. Journal / agency Uluc K, Kendigelen P, Fidan E, Zhang L, Chanana V, Kintner D, Akture E, Song C, Ye K, Sun D, Ferrazzano P, Cengiz P. TrkB receptor agonist 7, 8 dihydroxyflavone triggers profound gender- dependent neuroprotection in mice after perinatal hypoxia and ischemia. CNS Neurol Disord Drug Targets. 2013. doi:10.2174/18715273113129990061 · PMID 23469848 · PMC3674109
20. Journal / agency Tian M, Zeng Y, Hu Y, Yuan X, Liu S, Li J, Lu P, Sun Y, Gao L, Fu D, Li Y, Wang S, McClintock SM. 7, 8-Dihydroxyflavone induces synapse expression of AMPA GluA1 and ameliorates cognitive and spine abnormalities in a mouse model of fragile X syndrome. Neuropharmacology. 2015. doi:10.1016/j.neuropharm.2014.09.006 · PMID 25229717
21. Journal / agency Johnson RA, Lam M, Punzo AM, Li H, Lin BR, Ye K, Mitchell GS, Chang Q. 7,8-dihydroxyflavone exhibits therapeutic efficacy in a mouse model of Rett syndrome. J. Appl. Physiol. 2012. doi:10.1152/japplphysiol.01361.2011 · PMID 22194327 · PMC3643819
22. Journal / agency Zeng Y, Lv F, Li L, Yu H, Dong M, Fu Q. 7,8-dihydroxyflavone rescues spatial memory and synaptic plasticity in cognitively impaired aged rats. J. Neurochem. 2012. doi:10.1111/j.1471-4159.2012.07830.x · PMID 22694088
23. Journal / agency Bollen E, Vanmierlo T, Akkerman S, Wouters C, Steinbusch HM, Prickaerts J. 7,8-Dihydroxyflavone improves memory consolidation processes in rats and mice. Behav. Brain Res. 2013. doi:10.1016/j.bbr.2013.09.029 · PMID 24070857
24. Journal / agency Andero R, Heldt SA, Ye K, Liu X, Armario A, Ressler KJ. Effect of 7,8-dihydroxyflavone, a small-molecule TrkB agonist, on emotional learning. Am J Psychiatry. 2011. doi:10.1176/appi.ajp.2010.10030326 · PMID 21123312 · PMC3770732
25. Journal / agency Foti M, Piattelli M, Baratta MT, Ruberto G. Flavonoids, Coumarins, and Cinnamic Acids as Antioxidants in a Micellar System. Structure−Activity Relationship†. Journal of Agricultural and Food Chemistry. 1996. doi:10.1021/jf950378u
26. Journal / agency Chen J, Chua KW, Chua CC, Yu H, Pei A, Chua BH, Hamdy RC, Xu X, Liu CF. Antioxidant activity of 7,8-dihydroxyflavone provides neuroprotection against glutamate-induced toxicity. Neurosci. Lett. 2011. doi:10.1016/j.neulet.2011.05.054 · PMID 21651962
27. Journal / agency Han X, Zhu S, Wang B, Chen L, Li R, Yao W, Qu Z. Antioxidant action of 7,8-dihydroxyflavone protects PC12 cells against 6-hydroxydopamine-induced cytotoxicity. Neurochem. Int. 2014. doi:10.1016/j.neuint.2013.10.018 · PMID 24220540
28. Journal / agency Zhang R, Kang KA, Piao MJ, Ko DO, Wang ZH, Chang WY, You HJ, Lee IK, Kim BJ, Kang SS, Hyun JW. Preventive effect of 7,8-dihydroxyflavone against oxidative stress induced genotoxicity. Biol. Pharm. Bull. 2009. doi:10.1248/bpb.32.166 · PMID 19182370
29. Journal / agency Ren Q, Zhang JC, Ma M, Fujita Y, Wu J, Hashimoto K. 7,8-Dihydroxyflavone, a TrkB agonist, attenuates behavioral abnormalities and neurotoxicity in mice after administration of methamphetamine. Psychopharmacology. 2014. doi:10.1007/s00213-013-3221-7 · PMID 23934209
30. Journal / agency Boltaev U, Meyer Y, Tolibzoda F, Jacques T, Gassaway M, Xu Q, Wagner F, Zhang YL, Palmer M, Holson E, Sames D. Multiplex quantitative assays indicate a need for reevaluating reported small-molecule TrkB agonists. Sci Signal. 2017. doi:10.1126/scisignal.aal1670 · PMID 28831019
31. Journal / agency Todd D, Gowers I, Dowler SJ, Wall MD, McAllister G, Fischer DF, Dijkstra S, Fratantoni SA, van de Bospoort R, Veenman-Koepke J, Flynn G, Arjomand J, Dominguez C, Munoz-Sanjuan I, Wityak J, Bard JA. A monoclonal antibody TrkB receptor agonist as a potential therapeutic for Huntington's disease. PLOS ONE. 2014. doi:10.1371/journal.pone.0087923 · PMID 24503862 · PMC3913682
32. Journal / agency Kao YC, Zhou C, Sherman M, Laughton CA, Chen S. Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study. Environ. Health Perspect. 1998. doi:10.1289/ehp.9810685 · PMID 9435150 · PMC1533021
33. Journal / agency Le Bail JC, Laroche T, Marre-Fournier F, Habrioux G. Aromatase and 17beta-hydroxysteroid dehydrogenase inhibition by flavonoids. Cancer Letters. November 1998. doi:10.1016/S0304-3835(98)00211-0 · PMID 9929167
34. Journal / agency Le Bail JC, Varnat F, Nicolas JC, Habrioux G. Estrogenic and antiproliferative activities on MCF-7 human breast cancer cells by flavonoids. Cancer Lett. 1998. doi:10.1016/S0304-3835(98)00141-4 · PMID 9751276
35. Journal / agency Pouget C, Lauthier F, Simon A, Fagnere C, Basly JP, Delage C, Chulia AJ. Flavonoids: structural requirements for antiproliferative activity on breast cancer cells. Bioorg. Med. Chem. Lett. 2001. doi:10.1016/S0960-894X(01)00617-5 · PMID 11720850
36. Journal / agency Feng P, Akladious AA, Hu Y, Raslan Y, Feng J, Smith PJ. 7,8-Dihydroxyflavone reduces sleep during dark phase and suppresses orexin A but not orexin B in mice. Journal of Psychiatric Research. October 2015. doi:10.1016/j.jpsychires.2015.08.002 · PMID 26343602

Text and values on this page are quoted from Wikipedia (CC BY-SA 4.0), PubChem (public domain). Each value links to the exact revision it came from.