6-Methylflavone, a benzodiazepine receptor ligand with antagonistic properties on rat brain and human recombinant GABA(A) receptors in vitro

Seventeen flavonoids were found to have inhibitory activity on the central nervous system GABA(A)/benzodiazepine (BZD) receptors with IC 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 GABA(A)/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 [ H]-Ro 15-1 788, binding to rat brain cortical membranes. The GABA ratio of 1.06 for [ H]-diazepam binding to cortex and 1.23 for cerebellum indicated an antagonistic or a weak partial agonistic profile of 6-methylflavone on the rat BZD receptors, while the GABA ratio of 0.76 on hippocampus indicated an antagonistic or partial-inverse agonistic profile on the BZD receptors. In Sf-9 insects cells, the GABA ratios showed a weak partial agonistic profile on the α β γ(2S) (GABA ratio 1.29) subtype combination, an antagonistic profile on the α β γ(2S) (1.13) and α β γ(2S) (1.03), and a partial inverse agonistic profile on the α β γ(2S) (0.79) subtype combination. The modulation of GABA-induced chloride currents by 6-methylflavone suggests that the compound is an antagonist at human GABA(A) receptor subtypes. Based on our data of GABA(A)/BZD receptor active as well as inactive flavonoids, some general structure-activity relationships are discussed. 50 1 2 1 2 2 2 3 2 5 2 3