Flumazenil-independent positive modulation of gamma-aminobutyric acid action by 6-methylflavone at human recombinant alpha1beta2gamma2L and alpha1beta2 GABAA receptors.
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.
Hall
Belinda J
BJ
Adrien Albert Laboratory of Medicinal Chemistry, Department of Pharmacology, Faculty of Medicine, University of Sydney, Sydney, NSW 2006, Australia.
Chebib
Mary
M
Hanrahan
Jane R
JR
Johnston
Graham A R
GA
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*
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