Tropoflavin
Chemical compound
From Wikipedia, the free encyclopedia
Tropoflavin, also known as 7,8-dihydroxyflavone (7,8-DHF), is a naturally occurring flavone found in Godmania aesculifolia, Tridax procumbens, and Primula vulgaris.[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]
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| Other names | 7,8-Dihydroxyflavone; 7,8-DHF |
| Pharmacokinetic data | |
| Bioavailability | ~5% (in mice)[1] |
| Elimination half-life | < 30 minutes (in mice)[1] |
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| ECHA InfoCard | 100.048.903 |
| Chemical and physical data | |
| Formula | C15H10O4 |
| Molar mass | 254.241 g·mol−1 |
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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), although 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]