Flavonoids benzodiazepine receptor

Salah SM, Jager AK. Two flavonoids from Artemisia herba-alba with in vitro GABAa-benzodiazepine receptor activity. J Ethnopharmacol 2005 99 145-146. 

Perhaps the most studied constituent of passionflower is the flavonoid chrysin. Chiysin was isolated from P. coeruiea, a species closely related to P. incarnata. It binds to benzodiazepine receptors with micromolar affinity (Ki = 3 pM) and competes for binding with the benzodiazepine flunitrazepam (Medina et al. 1990). Behavioral assays (see below) suggest that chrysin acts as a partial agonist at central benzodiazepine receptors (Wolfman et al. 1994). 

Sedative and anxioiytic effects A number of flavonoids have been shown to bind to benzodiazepine receptors and have anxiolytic effects (Medina et al. 1997). The anxiolytic effects of chrysin were examined in mice (Wolfman et al. 1994). Chrysin (1 mg/kg IP) reduces behavioral measures of anxiety (elevated-plus maze) in a manner similar to diazepam (0.3-0.6 mg/kg), which was reversed by pretreatment with a benzodiazepine antagonist, Ro 15-1788. The anxiolytic effect is not likely due to sedation because there is no concurrent reduction in motor activity at the doses used. Unlike diazepam, chrysin does not produce muscle relaxation at higher doses. 

Medina JH, Viola H, Wolfman C, Marder M, Wasowski C, Calvo D, Paladini AC. (1997). Overview— flavonoids a new family of benzodiazepine receptor ligands. Neurochem Res. 22(4) 419-25. Menghini A, Mancini LA. (1988). TLC determination of flavonoid accumulation in clonal populations of Passiflora incarnata L. Pharmacol Res Commun. 20(suppl 5) 113-16. 

Salgueiro JB, Ardenghi P, Dias M, Ferreira MB, Izquierdo I, Medina JH. (1997). Anxiolytic natural and synthetic flavonoid ligands of the central benzodiazepine receptor have no effect on memory tasks in rats. Pharmacol Blochem Behav. 58(4) 887-91. 

The available pharmacological studies generally support, with some conflicting results, the empirically acknowledged sedative and anxiolytic effects of Passiflora, but it is not yet clear which constituents are responsible for these actions. One possibility which has received attention is related to the ability of flavonoids to bind to benzodiazepine receptors. The acute toxicity is very low. 

Some naturally occurring flavonoids, as well as the flavone nucleus itself, were found to be ligands to central benzodiazepine receptors (BDZ-Rs). In the search for new compounds with afQnity for the BDZ-Rs, Marder and coworkers described a solution-phase synthesis of flavone derivatives (Figure 11.82). In a three-step sequence, mixtures containing equimolar amounts of four... 

FIGURE 11.82 Library of flavonoids with affinity for benzodiazepine receptors. (From Marder, M. et aL, Detection of benzodiazepine receptor hgands in small hbraries of flavone derivatives synthesized hy solution phase combinatorial chemistry, Biochem. Biophys. Res. Commun., 249, 481, 1998.)... 

Medina JH, Viola H, Wolfinan C, Marder M, Wasowski C, Calvo D, Paladini AC. Overview flavonoids a new family of benzodiazepine receptor ligands. Neurochem Res 1997 22(4) 419-425. 

Recent interest has been directed to the use of flavonoids and flavonoid derivatives as benzodiazepine receptor (BDZ-R) ligands [159]. Benzodiazepines... 

Huang, X. et al., 3D-QSAR model of flavonoids binding at benzodiazepine site in GABAa receptors, J. Med. Chem., 44, 1883, 2001. 

The classical hydrogen-donating antioxidant properties of flavonoids, which are often used as a possible explanation for their biological activity, may, after all, not be the most important determinant for their effects in vivo. This conclusion is tenable when faetors sueh as in vivo metaboUsm and the achieved plasma and tissue coneentrations of flavonoids/metabolites are taken into account. Therefore, the bioaetivity of flavonoids in vivo may rather be supported by their ability to modulate protein fimctions, intracellular cell signaling, and receptor activities on the basis of interactions, for example, with ATP-binding sites and benzodiazepine-binding domains. 

Dekermendjian K, Kahnherg P, Witt MR, Sterner O, Nielsen M, Liljefors T. Structure-activity relationships and molecular modeling analysis of flavonoids binding to the benzodiazepine site of the rat brain GABA(A) receptor complex. J Med Chem 1999 42(21) 4343 350. 

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