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Naturally occurring 2′-hydroxyl-substituted flavonoids as high-affinity benzodiazepine site ligands

2003; Elsevier BV; Volume: 66; Issue: 12 Linguagem: Inglês

10.1016/j.bcp.2003.08.016

1873-2968

Michael S.Y. Huen, Kwok‐Min Hui, Justin Leung, Erwin Sigel, Roland Baur, J. Tze‐Fei Wong, Hong Xue,

Receptor Mechanisms and Signaling

Screening of traditional medicines has proven invaluable to drug development and discovery. Utilizing activity-guided purification, we previously reported the isolation of a list of flavonoids from the medicinal herb Scutellaria baicalensis Georgi, one of which manifested an affinity for the benzodiazepine receptor (BDZR) comparable to that of the synthetic anxiolytic diazepam (Ki=6.4 nM). In the present study, this high-affinity, naturally occurring flavonoid derivative, 5,7,2′-trihydroxy-6,8-dimethoxyflavone (K36), was chosen for further functional and behavioral characterization. K36 inhibited [3H]flunitrazepam binding to native BDZR with a Ki value of 6.05 nM. In electrophysiological experiments K36 potentiated currents mediated by rat recombinant α1β2γ2 GABAA receptors expressed in Xenopus oocytes. This potentiation was characterized by a threshold (1 nM) and half-maximal stimulation (24 nM) similar to diazepam. This enhancement was demonstrated to act via the BDZR, since co-application of 1 μM of the BDZR antagonist Ro15-1788 reversed the potentiation. Oral administration of K36 produced significant BDZR-mediated anxiolysis in the mice elevated plus-maze, which was abolished upon co-administration of Ro15-1788. Sedation, myorelaxation and motor incoordination were not observed in the chosen dosage regimen. Structure–activity relationships utilizing synthetic flavonoids with different 2′ substituents on the flavone backbone supported that 2′-hydroxyl-substitution is a critical moiety on flavonoids with regard to BDZR affinities. These results further underlined the potential of flavonoids as therapeutics for the treatment of BDZR-associated syndromes.