6-Methylflavanone, a more efficacious positive allosteric modulator of γ-aminobutyric acid (GABA) action at human recombinant α 2β 2γ 2L than at α 1β 2γ 2L and α 1β 2 GABA A receptors expressed in Xenopus oocytes

Abstract

6-Methylflavanone acted as a positive allosteric modulator of γ-aminobutyric acid (GABA) responses at human recombinant α 1β 2γ 2L, α 2β 2γ 2L and α 1β 2 GABA A receptors expressed in Xenopus laevis oocytes. It was essentially inactive at ρ 1 GABA C receptors. The EC 50 values for 6-methylflavanone for the positive modulation of the EC 10–20 GABA responses were 22 μM, 10 μM and 6 μM and the maximum potentiations were 120%, 417% and 130% at α 1β 2γ 2L, α 2β 2γ 2L and α 1β 2 GABA A receptors respectively. Thus 6-methylflavanone was much more efficacious as a positive modulator at α 2β 2γ 2L than at α 1β 2γ 2L and α 1β 2 GABA A receptors. This may be significant since diazepam-induced anxiolysis is considered to be mediated via α 2-containing GABA A receptors, while sedation is thought to be mediated via α 1-containing GABA A receptors. We have previously reported that 6-methylflavone (1–100 μM) produced positive allosteric modulation at α 1β 2γ 2L and α 1β 2 GABA A receptors with no significant difference between the enhancement seen at either receptor subtype. In the present study, 6-methylflavone was tested at α 2β 2γ 2L GABA A receptors and found to maximally potentiate the EC 10–20 GABA response by 183 ± 39% which is similar to that previously observed for 6-methylflavone at α 1β 2γ 2L GABA A receptors. Thus, 6-methylflavone did not show a preference for α 2β 2γ 2L over α 1β 2γ 2L GABA A receptors in terms of efficacy. Compared to 6-methylflavone, 6-methylflavanone is more efficacious as a positive allosteric modulator at α 2β 2γ 2L GABA A receptors, and less efficacious at α 1β 2γ 2L GABA A receptors. This may represent a relatively unique type of selectivity for positive modulators of GABA-A receptor subtypes based on efficacy as distinct from potency. As was previously shown for 6-methylflavone at α 1β 2γ 2L GABA A receptors, the positive modulation of GABA responses at α 1β 2γ 2L and α 2β 2γ 2L GABA A receptors by 6-methylflavanone was insensitive to antagonism by flumazenil, indicating that this action is not mediated via “high-affinity” benzodiazepine sites.