Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Br J Pharmacol
2012 Feb 01;1654:880-96. doi: 10.1111/j.1476-5381.2011.01604.x.
Show Gene links
Show Anatomy links
2'-Methoxy-6-methylflavone: a novel anxiolytic and sedative with subtype selective activating and modulating actions at GABA(A) receptors.
Karim N
,
Curmi J
,
Gavande N
,
Johnston GA
,
Hanrahan JR
,
Tierney ML
,
Chebib M
.
???displayArticle.abstract???
Flavonoids are known to have anxiolytic and sedative effects mediated via actions on ionotropic GABA receptors. We sought to investigate this further.We evaluated the effects of 2'-methoxy-6-methylflavone (2'MeO6MF) on native GABA(A) receptors in new-born rat hippocampal neurons and determined specificity from 18 human recombinant GABA(A) receptor subtypes expressed in Xenopus oocytes. We used ligand binding, two-electrode voltage clamp and patch clamp studies together with behavioural studies.2'MeO6MF potentiated GABA at α2β1γ2L and all α1-containing GABA(A) receptor subtypes. At α2β2/3γ2L GABA(A) 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 β1/2 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 GABA(A) Cl(-) currents. In the continued presence of 2'MeO6MF the single-channel conductance increased and these high conductance channels were disrupted by the γ2(381-403) MA peptide, indicating that such currents are mediated by α2/γ2-containing GABA(A) 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.2'MeO6MF will serve as a tool to study the complex nature of the activation and modulation of GABA(A) receptor subtypes.
Alexander,
Guide to Receptors and Channels (GRAC), 5th edition.
2011, Pubmed
Alexander,
Guide to Receptors and Channels (GRAC), 5th edition.
2011,
Pubmed
Atack,
GABAA receptor subtype-selective modulators. II. α5-selective inverse agonists for cognition enhancement.
2011,
Pubmed
Atack,
GABAA receptor subtype-selective modulators. I. α2/α3-selective agonists as non-sedating anxiolytics.
2011,
Pubmed
Atack,
The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics.
2005,
Pubmed
Belelli,
The interaction of the general anesthetic etomidate with the gamma-aminobutyric acid type A receptor is influenced by a single amino acid.
1997,
Pubmed
,
Xenbase
Boileau,
The relative amount of cRNA coding for gamma2 subunits affects stimulation by benzodiazepines in GABA(A) receptors expressed in Xenopus oocytes.
2002,
Pubmed
,
Xenbase
Bonetti,
Benzodiazepine antagonist Ro 15-1788: neurological and behavioral effects.
1982,
Pubmed
Bourin,
The mouse light/dark box test.
2003,
Pubmed
Caraiscos,
Selective enhancement of tonic GABAergic inhibition in murine hippocampal neurons by low concentrations of the volatile anesthetic isoflurane.
2004,
Pubmed
Chebib,
Novel, potent, and selective GABAC antagonists inhibit myopia development and facilitate learning and memory.
2009,
Pubmed
,
Xenbase
Crestani,
Molecular targets for the myorelaxant action of diazepam.
2001,
Pubmed
Crestani,
Trace fear conditioning involves hippocampal alpha5 GABA(A) receptors.
2002,
Pubmed
Curmi,
The influence of membrane potential on chloride channels activated by GABA in rat cultured hippocampal neurons.
1993,
Pubmed
Desai,
Gamma-amino butyric acid type A receptor mutations at beta2N265 alter etomidate efficacy while preserving basal and agonist-dependent activity.
2009,
Pubmed
,
Xenbase
Eghbali,
Effects of propofol on GABAA channel conductance in rat-cultured hippocampal neurons.
2003,
Pubmed
Eghbali,
Hippocampal GABA(A) channel conductance increased by diazepam.
1997,
Pubmed
Everitt,
Protein interactions involving the gamma2 large cytoplasmic loop of GABA(A) receptors modulate conductance.
2009,
Pubmed
Farrant,
Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors.
2005,
Pubmed
Fernandez,
Flavan-3-ol derivatives are positive modulators of GABA(A) receptors with higher efficacy for the alpha(2) subtype and anxiolytic action in mice.
2008,
Pubmed
,
Xenbase
Ferrini,
Neuro-pharmacological studies on SB 5833, a new psychotherapeutic agent of the benzodiazepine class.
1974,
Pubmed
File,
The effects of triazolobenzodiazepines in two animal tests of anxiety and in the holeboard.
1985,
Pubmed
Gamet-Payrastre,
Flavonoids and the inhibition of PKC and PI 3-kinase.
1999,
Pubmed
Gee,
Limiting activity at beta1-subunit-containing GABAA receptor subtypes reduces ataxia.
2010,
Pubmed
,
Xenbase
Groves,
The role of GABAbeta2 subunit-containing receptors in mediating the anticonvulsant and sedative effects of loreclezole.
2006,
Pubmed
Hall,
Flumazenil-independent positive modulation of gamma-aminobutyric acid action by 6-methylflavone at human recombinant alpha1beta2gamma2L and alpha1beta2 GABAA receptors.
2004,
Pubmed
,
Xenbase
Hall,
6-Methylflavanone, a more efficacious positive allosteric modulator of gamma-aminobutyric acid (GABA) action at human recombinant alpha2beta2gamma2L than at alpha1beta2gamma2L and alpha1beta2 GABA(A) receptors expressed in Xenopus oocytes.
2005,
Pubmed
,
Xenbase
Halliwell,
Subunit-selective modulation of GABAA receptors by the non-steroidal anti-inflammatory agent, mefenamic acid.
1999,
Pubmed
,
Xenbase
Hanrahan,
Flavonoid modulation of GABA(A) receptors.
2011,
Pubmed
Herd,
The expression of GABAA beta subunit isoforms in synaptic and extrasynaptic receptor populations of mouse dentate gyrus granule cells.
2008,
Pubmed
Hill-Venning,
Subunit-dependent interaction of the general anaesthetic etomidate with the gamma-aminobutyric acid type A receptor.
1997,
Pubmed
,
Xenbase
Hodge,
Decreased anxiety-like behavior, reduced stress hormones, and neurosteroid supersensitivity in mice lacking protein kinase Cepsilon.
2002,
Pubmed
Hosie,
Zinc-mediated inhibition of GABA(A) receptors: discrete binding sites underlie subtype specificity.
2003,
Pubmed
Huang,
Pentylenetetrazole-induced inhibition of recombinant gamma-aminobutyric acid type A (GABA(A)) receptors: mechanism and site of action.
2001,
Pubmed
,
Xenbase
Irwin,
Comprehensive observational assessment: Ia. A systematic, quantitative procedure for assessing the behavioral and physiologic state of the mouse.
1968,
Pubmed
Jiang,
Retrochalcone derivatives are positive allosteric modulators at synaptic and extrasynaptic GABA(A) receptors in vitro.
2011,
Pubmed
Jäger,
Flavonoids and the CNS.
2011,
Pubmed
Kahnberg,
Refinement and evaluation of a pharmacophore model for flavone derivatives binding to the benzodiazepine site of the GABA(A) receptor.
2002,
Pubmed
Lambert,
Neurosteroid modulation of native and recombinant GABAA receptors.
1996,
Pubmed
Lippa,
Selective anxiolysis produced by ocinaplon, a GABA(A) receptor modulator.
2005,
Pubmed
,
Xenbase
Löw,
Molecular and neuronal substrate for the selective attenuation of anxiety.
2000,
Pubmed
Maitra,
Modulation of GABA(A) receptor function by neuroactive steroids: evidence for heterogeneity of steroid sensitivity of recombinant GABA(A) receptor isoforms.
1998,
Pubmed
,
Xenbase
Mangan,
Cultured Hippocampal Pyramidal Neurons Express Two Kinds of GABAA Receptors.
2005,
Pubmed
Mattila,
Determination of flavonoids in plant material by HPLC with diode-array and electro-array detections.
2000,
Pubmed
McKernan,
Which GABAA-receptor subtypes really occur in the brain?
1996,
Pubmed
Mihalek,
Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice.
1999,
Pubmed
Nilsson,
Modulation of GABA(A) receptors by natural products and the development of novel synthetic ligands for the benzodiazepine binding site.
2011,
Pubmed
Olsen,
GABA A receptors: subtypes provide diversity of function and pharmacology.
2009,
Pubmed
Orser,
Propofol modulates activation and desensitization of GABAA receptors in cultured murine hippocampal neurons.
1994,
Pubmed
Popik,
The anxioselective agent 7-(2-chloropyridin-4-yl)pyrazolo-[1,5-a]-pyrimidin-3-yl](pyridin-2-yl)methanone (DOV 51892) is more efficacious than diazepam at enhancing GABA-gated currents at alpha1 subunit-containing GABAA receptors.
2006,
Pubmed
,
Xenbase
Ransom,
Cooperative modulation of [3H]MK-801 binding to the N-methyl-D-aspartate receptor-ion channel complex by L-glutamate, glycine, and polyamines.
1988,
Pubmed
Ren,
GABA(A) receptor subtype selectivity underlying anxiolytic effect of 6-hydroxyflavone.
2010,
Pubmed
Rudolph,
Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes.
1999,
Pubmed
Seymour,
Differential drug responses on native GABA(A) receptors revealing heterogeneity in extrasynaptic populations in cultured hippocampal neurons.
2009,
Pubmed
Sieghart,
Structure, pharmacology, and function of GABAA receptor subtypes.
2006,
Pubmed
Thompson,
Barbiturate interactions at the human GABAA receptor: dependence on receptor subunit combination.
1996,
Pubmed
,
Xenbase
Tierney,
Insights into the biophysical properties of GABA(A) ion channels: modulation of ion permeation by drugs and protein interactions.
2011,
Pubmed
Wang,
6,2'-Dihydroxyflavone, a subtype-selective partial inverse agonist of GABAA receptor benzodiazepine site.
2007,
Pubmed
Whiting,
GABA-A receptors: a viable target for novel anxiolytics?
2006,
Pubmed
