title: Flumazenil-independent positive modulation of gamma-aminobutyric acid action by 6-methylflavone at human recombinant alpha1beta2gamma2L and alpha1beta2 GABAA receptors.
abstract: In view of the ability of flavones to displace radiolabelled benzodiazepines from brain tissue and the interesting behavioural profile of these compounds, the present study investigated the activity of 6-methylflavone at ionotropic gamma-aminobutyric acid (GABA) receptors expressed in Xenopus laevis oocytes. 6-Methylflavone (1-100 microM) was found to be a positive allosteric modulator at alpha1beta2gamma2L and alpha1beta2 GABAA receptors with no significant difference between the enhancement seen at either receptor subtype. At 100 microM, 6-methylflavone enhanced the response to 5 microM GABA by 183+/-20% at alpha1beta2gamma2L GABAA receptors. The methyl substituent was important since the parent flavone was significantly weaker as a positive modulator (103+/-24% enhancement of 5 microM GABA by 100 microM flavone). This enhancement is not mediated via high-affinity benzodiazepine sites as it was not inhibited by the classical benzodiazepine antagonist flumazenil under conditions where flumazenil inhibits the potentiation of the GABA response to diazepam. 6-Methylflavone (60 microM) did not significantly affect the GABA dose-response curve at rho1 GABAC receptors. 6-Methylflavone acts as a positive modulator of recombinant GABAA receptors at sites independent of flumazenil-sensitive benzodiazepine sites.
authors.affiliation: Adrien Albert Laboratory of Medicinal Chemistry, Department of Pharmacology, Faculty of Medicine, University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Belinda J
authors.initials: BJ
authors.lastname: Hall
authors.forename: Mary
authors.initials: M
authors.lastname: Chebib
authors.forename: Jane R
authors.initials: JR
authors.lastname: Hanrahan
authors.forename: Graham A R
authors.initials: GA
authors.lastname: Johnston
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D047309:Flavones / Q000737:chemistry / Q000494:pharmacology*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008845:Microinjections; D015394:Molecular Structure; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D012313:RNA / Q000008:administration & dosage / Q000235:genetics; D018079:Receptors, GABA / Q000235:genetics / Q000502:physiology; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: C493089:6-methylflavone; D047309:Flavones; D005419:Flavonoids; D018757:GABA Modulators; C087200:GABA-C receptor; D021122:Protein Subunits; D018079:Receptors, GABA; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D012313:RNA; D003975:Diazepam; C043562:flavone