Eur J Pharmacol 2004 Apr 26;4911:1-8. doi: 10.1016/j.ejphar.2004.03.014.

Flumazenil-independent positive modulation of gamma-aminobutyric acid action by 6-methylflavone at human recombinant alpha1beta2gamma2L and alpha1beta2 GABAA receptors.

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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.

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Species referenced: Xenopus laevis
Genes referenced: gabarap