6-Methylflavanone, a more efficacious positive allosteric modulator of γ-aminobutyric acid (GABA) action at human recombinant α2β2γ2L than at α1β2γ2L and α1β2GABAA receptors expressed in Xenopus oocytes

6-Methylflavanone acted as a positive allosteric modulator of gamma-aminobutyric acid (GABA) responses at human recombinant alpha(1)beta(2)gamma(2L), alpha(1)beta(2)gamma(2L) and alpha(1)beta(2) GABA(A) receptors expressed in Xenopus laevis oocytes. It was essentially inactive at rho(1) GABA(C) receptors. The EC50 values for 6-methylflavanone for the positive modulation of the EC10-20 GABA responses were 22 mu M, 10 mu M and 6 mu M and the maximum potentiations were 120%, 417% and 130% at a alpha(1)beta(2)gamma(2L), alpha(1)beta(2)gamma(2L) and alpha(1)beta(2) GABA(A) receptors respectively. Thus 6-methylflavanone was much more efficacious as a positive modulator at alpha(1)beta(2)gamma(2L) than at alpha(1)beta(2)gamma(2L) and alpha(1)beta(2) GABA(A) receptors. This may be significant since diazepam-induced anxiolysis is considered to be mediated via alpha(2)-containing GABA(A) receptors, while sedation is thought to be mediated via alpha(1)-containing GABA(A) receptors. We have previously reported that 6-methylflavone (1-100 mu M) produced positive allosteric modulation at a alpha(1)beta(2)gamma(2L) and alpha(1)beta(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 alpha(2)beta(2)gamma(2L) GABA(A) receptors and found to maximally potentiate the EC10-20 GABA response by 183 +/- 39% which is similar to that previously observed for 6-methylflavone at alpha(1)beta(2)gamma(2L) GABA(A) receptors. Thus, 6-methylflavone did not show a preference for alpha(2)beta(2)gamma(2L) over alpha(1)beta(1)gamma(2L) GABA(A) receptors in terms of efficacy. Compared to 6-methylflavone, 6-methylflavanone is more efficacious as a positive allosteric modulator at alpha(2)beta(2)gamma(2L) GABA(A) receptors, and less efficacious at alpha(1)beta(2)gamma(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 a alpha(1)beta(2)gamma(2L) GABA(A) receptors, the positive modulation of GABA responses at alpha(1)beta(2)gamma(2L) and alpha(2)beta(2)gamma(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. (c) 2005 Elsevier B.V. All rights reserved.