Flumazenil-independent positive modulation of γ-aminobutyric acid action by 6-methylflavone at human recombinant α 1β 2γ 2L and α 1β 2 GABA A receptors

Abstract

In view of the ability of flavones to displace radiolabelled benzodiazepines from brain tissue and the interesting behavioural profile of these compounds, the present study investigated the activity of 6-methylflavone at ionotropic γ-aminobutyric acid (GABA) receptors expressed in Xenopus laevis oocytes. 6-Methylflavone (1–100 μM) was found to be a positive allosteric modulator at α 1β 2γ 2L and α 1β 2 GABA A receptors with no significant difference between the enhancement seen at either receptor subtype. At 100 μM, 6-methylflavone enhanced the response to 5 μM GABA by 183±20% at α 1β 2γ 2L GABA A receptors. The methyl substituent was important since the parent flavone was significantly weaker as a positive modulator (103±24% enhancement of 5 μM GABA by 100 μM flavone). This enhancement is not mediated via high-affinity benzodiazepine sites as it was not inhibited by the classical benzodiazepine antagonist flumazenil under conditions where flumazenil inhibits the potentiation of the GABA response to diazepam. 6-Methylflavone (60 μM) did not significantly affect the GABA dose–response curve at ρ 1 GABA C receptors. 6-Methylflavone acts as a positive modulator of recombinant GABA A receptors at sites independent of flumazenil-sensitive benzodiazepine sites.