Seventeen flavonoids were found to have inhibitory activity on the central nervous system GABAA/benzodiazepine (BZD) receptors with IC50 values ranging from 0.12 to 8 μM. 6-Methylflavone, the most potent, was pharmacologically characterized by radioligand binding assays on rat brain membranes in vitro and human recombinant GABAA/BZD receptors expressed in Sf-9 insect cells, as well as electrophysiologically by the whole-cell patch clamp technique. Scatchard plot analysis showed that 6-methylflavone was a competitive inhibitor of [3H]-Ro 15-1788, binding to rat brain cortical membranes. The GABA ratio of 1.06 for [3H]-diazepam binding to cortex and 1.23 for cerebellum indicated an antagonistic or a weak partial agonistic profile of 6-methylflavone on the rat BZD1 receptors, while the GABA ratio of 0.76 on hippocampus indicated an antagonistic or partial-inverse agonistic profile on the BZD2 receptors. In Sf-9 insects cells, the GABA ratios showed a weak partial agonistic profile on the α1β2γ2S (GABA ratio 1.29) subtype combination, an antagonistic profile on the α2β2γ2S (1.13) and α3β2γ2S (1.03), and a partial inverse agonistic profile on the α5β2γ2S (0.79) subtype combination. The modulation of GABA-induced chloride currents by 6-methylflavone suggests that the compound is an antagonist at human GABAA receptor subtypes. Based on our data of GABAA/BZD receptor active as well as inactive flavonoids, some general structure–activity relationships are discussed. Drug Dev. Res. 41:99–106, 1997.
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Ai et al. (1997) studied this question.