Modulation of Ionotropic GABA Receptors by 6-Methoxyflavanone and 6-Methoxyflavone

We evaluated the effects of 6-methoxyflavanone and 6-methoxyflavone on wild-type alpha 1/alpha 2 beta 2 gamma 2L GABA(A) and rho 1 GABA(C) receptors and on mutant rho 1I307S, rho 1W328 M, rho 1I307S/W328 M GABA(C) receptors expressed in Xenopus oocytes using two-electrode voltage clamp and radioligand binding. 6-Methoxyflavanone and 6-methoxyflavone act as a flumazenil-insensitive positive allosteric modulator of GABA responses at human recombinant alpha 1 beta 2 gamma 2L and alpha 2 beta 2 gamma 2L GABA(A) receptors. However, unlike 6-methoxyflavone, 6-methoxyflavanone was relatively inactive at alpha 1 beta 2 GABA(A) receptors. 6-Methoxyflavanone inhibited [H-3]-flunitrazepam binding to rat brain membranes. Both flavonoids were found to be inactive as modulators at rho 1, rho 1I307S and rho 1W328 M GABA receptors but acted as positive allosteric modulators of GABA at the benzodiazepine sensitive rho 1I307S/W328 M GABA receptors. This double mutant retains rho 1 properties of being insensitive to bicuculline and antagonised by TPMPA and THIP. Additionally, 6-methoxyflavanone was also a partial agonist at rho 1W328 M GABA receptors. The relative inactivity of 6-methoxyflavanone at alpha 1 beta 2 GABA(A) receptors and it's partial agonist action at rho 1W328 M GABA receptors suggest that it exhibits a unique profile not matched by other flavonoids.