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

6-Methylflavanone acted as a positive allosteric modulator of gamma -aminobutyric acid (GABA) responses at human recombinant alpha sub(1) beta sub(2) gamma sub(2L), alpha sub(2) beta sub(2) gamma sub(2L) and alpha sub(1) beta sub(2) GABA sub(A) receptors expressed in Xenopus laevis oocytes. It was essentially inactive at rho sub(1) GABA sub(C) receptors. The EC sub(50) values for 6-methylflavanone for the positive modulation of the EC sub(10-20) GABA responses were 22 mu M, 10 mu M and 6 mu M and the maximum potentiations were 120%, 417% and 130% at alpha sub(1) beta sub(2) gamma sub(2L), alpha sub(2) beta sub(2) gamma sub(2L) and alpha sub(1) beta sub(2) GABA sub(A) receptors respectively. Thus 6-methylflavanone was much more efficacious as a positive modulator at alpha sub(2) beta sub(2) gamma sub(2L) than at alpha sub(1) beta sub(2) gamma sub(2L) and alpha sub(1) beta sub(2) GABA sub(A) receptors. This may be significant since diazepam-induced anxiolysis is considered to be mediated via alpha sub(2)-containing GABA sub(A) receptors, while sedation is thought to be mediated via alpha sub(1)-containing GABA sub(A) receptors. We have previously reported that 6-methylflavone (1-100 mu M) produced positive allosteric modulation at alpha sub(1) beta sub(2) gamma sub(2L) and alpha sub(1) beta sub(2) GABA sub(A) receptors with no significant difference between the enhancement seen at either receptor subtype. In the present study, 6-methylflavone was tested at alpha sub(2) beta sub(2) gamma sub(2L) GABA sub(A) receptors and found to maximally potentiate the EC sub(10-20) GABA response by 183 plus or minus 39% which is similar to that previously observed for 6-methylflavone at alpha sub(1) beta sub(2) gamma sub(2L) GABA sub(A) receptors. Thus, 6-methylflavone did not show a preference for alpha sub(2) beta sub(2) gamma sub(2L) over alpha sub(1) beta sub(2) gamma sub(2L) GABA sub(A) receptors in terms of efficacy. Compared to 6-methylflavone, 6-methylflavanone is more efficacious as a positive allosteric modulator at alpha sub(2) beta sub(2) gamma sub(2L) GABA sub(A) receptors, and less efficacious at alpha sub(1) beta sub(2) gamma sub(2L) GABA sub(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 alpha sub(1) beta sub(2) gamma sub(2L) GABA sub(A) receptors, the positive modulation of GABA responses a