2′‐Methoxy‐6‐methylflavone: a novel anxiolytic and sedative with subtype selective activating and modulating actions at GABA_A receptors

Abstract

BACKGROUND AND PURPOSEFlavonoids are known to have anxiolytic and sedative effects mediated via actions on ionotropic GABA receptors. We sought to investigate this further. EXPERIMENTAL APPROACHWe evaluated the effects of 2′-methoxy-6-methylflavone (2′MeO6MF) on native GABAA receptors in new-born rat hippocampal neurons and determined specificity from 18 human recombinant GABAA receptor subtypes expressed in Xenopus oocytes. We used ligand binding, two-electrode voltage clamp and patch clamp studies together with behavioural studies. KEY RESULTS2′MeO6MF potentiated GABA at a2b1g2L and all a1-containing GABAA receptor subtypes. At a2b2/3g2L GABAA receptors, however, 2′MeO6MF directly activated the receptors without potentiating GABA. This activation was attenuated by bicuculline and gabazine but not flumazenil indicating a novel site. Mutation studies showed position 265 in the b1/2 subunit was key to whether 2′MeO6MF was an activator or a potentiator. In hippocampal neurons, 2′MeO6MF directly activated single-channel currents that showed the hallmarks of GABAA Cl -currents. In the continued presence of 2′MeO6MF the single-channel conductance increased and these high conductance channels were disrupted by the g2(381-403) MA peptide, indicating that such currents are mediated by a2/g2-containing GABAA receptors. In mice, 2′MeO6MF (1-100 mg·kg -1 ; i.p.) displayed anxiolytic-like effects in two unconditioned models of anxiety: the elevated plus maze and light/dark tests. 2′MeO6MF induced sedative effects at higher doses in the holeboard, actimeter and barbiturate-induced sleep time tests. No myorelaxant effects were observed in the horizontal wire test. CONCLUSIONS AND IMPLICATIONS2′MeO6MF will serve as a tool to study the complex nature of the activation and modulation of GABAA receptor subtypes.

GABAA receptor modulation and neuropharmacological activities of viscosine isolated from Dodonaea viscosa (Linn)

“…Recently, its pharmacokinetic profile in animals was also reported (Khan et al, 2014b). Viscosine is structurally related to the CNS-active flavonoids, 2′-MeO6MF (Karim et al, 2012) and 3-OH2′ MeO6MF (Karim et al, 2011). Unlike 2′-MeO6MF and 3-OH2′ MeO6MF, viscosine has hydroxy groups on C5 and C7 and methoxy groups on C3 and C6 (Fig.…”

“…More recently flavonoids such as amentoflavone (Hanrahan et al, 2003), 6-methylflavone (Hall et al, 2004), 6-methylflavanone (Hall et al, 2005), 6-hydroxyflavone (Ren et al, 2010), 2′-methoxy-6-methylflavone (2′MeO6MF) (Karim et al, 2012) and 3-hydroxy-2′methoxy-6-methylflavone (3-OH-2′MeO6MF) (Karim et al, 2011) have been shown to modulate GABA A receptors and many exert anxiolytic effects in mouse models of anxiety.…”

Flavonoid Actions on Receptors for the Inhibitory Neurotransmitter GABA

“…2′-Methoxy-6-methyllavone has demonstrated anxiolytic efects in mice at 1 and 10 mg/kg using the elevated plus maze model of anxiety [54]. It was also found to act as a positive modulator at α2β1γ2L and all α1-containing GABA A receptor subtypes, demonstrated via recombinant GABA A receptors expressed in Xenopus oocytes [54].…”

“…It was also found to act as a positive modulator at α2β1γ2L and all α1-containing GABA A receptor subtypes, demonstrated via recombinant GABA A receptors expressed in Xenopus oocytes [54]. By contrast, it directly activated α2β2/3γ2L receptors without potentiating GABA [54].…”

“…It was also found to act as a positive modulator at α2β1γ2L and all α1-containing GABA A receptor subtypes, demonstrated via recombinant GABA A receptors expressed in Xenopus oocytes [54]. By contrast, it directly activated α2β2/3γ2L receptors without potentiating GABA [54]. Activation by 2′-methoxy-6-methyllavone was atenuated by bicuculline and gabazine but not lumazenil, indicating Flavonoid Actions on Receptors for the Inhibitory Neurotransmitter GABA http://dx.doi.org/10.5772/67971 343 a novel site of action.…”