6‐Methylflavone, a benzodiazepine receptor ligand with antagonistic properties on rat brain and human recombinant GABAA receptors in vitro

Abstract

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. © 1997 Wiley-Liss, Inc.