Biochem Pharmacol 2011 Dec 15;8212:1971-83. doi: 10.1016/j.bcp.2011.09.002.

3-Hydroxy-2'-methoxy-6-methylflavone: a potent anxiolytic with a unique selectivity profile at GABA(A) receptor subtypes.

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Genetic and pharmacological studies have demonstrated that α2- and α4-containing GABA(A) receptors mediate the anxiolytic effects of a number of agents. Flavonoids are a class of ligands that act at GABA(A) receptors and possess anxiolytic effects in vivo. Here we demonstrate that the synthetic flavonoid, 3-hydroxy-2'-methoxy-6-methylflavone (3-OH-2'MeO6MF) potentiates GABA-induced currents at recombinant α1/2β2, α1/2/4/6β1-3γ2L but not α3/5β1-3γ2L receptors expressed in Xenopus oocytes. The enhancement was evident at micromolar concentrations (EC(50) values between 38 and 106 μM) and occurred in a flumazenil-insensitive manner. 3-OH-2'MeO6MF displayed preference for β2/3- over β1-containing receptors with the highest efficacy observed at α2β2/3γ2L, displaying a 4-11-fold increase in efficacy over α2β1γ2L and α1/4/6-containing subtypes. In contrast, 3-OH-2'MeO6MF acted as a potent bicuculline-sensitive activator, devoid of potentiation effects at extrasynaptic α4β2/3δ receptors expressed in oocytes. The affinity of 3-OH-2'MeO6MF for α4β2/3δ receptors (EC(50) values between 1.4 and 2.5 μM) was 10-fold higher than at α4β1δ GABA(A) receptors. 3-OH-2'MeO6MF acted as a full agonist at α4β2/3δ (105% of the maximal GABA response) but as a partial agonist at α4β1δ (61% of the maximum GABA response) receptors. In mice, 3-OH-2'MeO6MF (1-100 mg/kg i.p.) induced anxiolytic-like effects in two unconditioned models of anxiety: the elevated plus maze and light/dark paradigms. No sedative or myorelaxant effects were detected using holeboard, actimeter and horizontal wire tests and only weak barbiturate potentiating effects on the loss of righting reflex test. Taken together, these data suggest that 3-OH-2'MeO6MF is an anxiolytic without sedative and myorelaxant effects acting through positive allosteric modulation of the α2β2/3γ2L and direct activation of α4β2/3δ GABA(A) receptor subtypes.

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