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.
Eur J Pharmacol
; 512(2-3): 97-104, 2005 Apr 11.
Article
em En
| MEDLINE
| ID: mdl-15840393
ABSTRACT
6-Methylflavanone acted as a positive allosteric modulator of gamma-aminobutyric acid (GABA) responses at human recombinant alpha1beta2gamma2L, alpha2beta2gamma2L and alpha1beta2 GABA(A) receptors expressed in Xenopus laevis oocytes. It was essentially inactive at rho1 GABA(C) receptors. The EC50 values for 6-methylflavanone for the positive modulation of the EC(10-20) GABA responses were 22 microM, 10 microM and 6 microM and the maximum potentiations were 120%, 417% and 130% at alpha1beta2gamma2L, alpha2beta2gamma2L and alpha1beta2 GABA(A) receptors respectively. Thus 6-methylflavanone was much more efficacious as a positive modulator at alpha2beta2gamma2L than at alpha1beta2gamma2L and alpha1beta2 GABA(A) receptors. This may be significant since diazepam-induced anxiolysis is considered to be mediated via alpha2-containing GABA(A) receptors, while sedation is thought to be mediated via alpha1-containing GABA(A) receptors. We have previously reported that 6-methylflavone (1-100 microM) produced positive allosteric modulation at alpha1beta2gamma2L and alpha1beta2 GABA(A) receptors with no significant difference between the enhancement seen at either receptor subtype. In the present study, 6-methylflavone was tested at alpha2beta2gamma2L GABA(A) receptors and found to maximally potentiate the EC(10-20) GABA response by 183+/-39% which is similar to that previously observed for 6-methylflavone at alpha1beta2gamma2L GABA(A) receptors. Thus, 6-methylflavone did not show a preference for alpha2beta2gamma2L over alpha1beta2gamma2L GABA(A) receptors in terms of efficacy. Compared to 6-methylflavone, 6-methylflavanone is more efficacious as a positive allosteric modulator at alpha2beta2gamma2L GABA(A) receptors, and less efficacious at alpha1beta2gamma2L GABA(A) receptors. This may represent a relatively unique type of selectivity for positive modulators of GABA-A receptor subtypes based on efficacy as distinct from potency. As was previously shown for 6-methylflavone at alpha1beta2gamma2L GABA(A) receptors, the positive modulation of GABA responses at alpha1beta2gamma2L and alpha2beta2gamma2L GABA(A) receptors by 6-methylflavanone was insensitive to antagonism by flumazenil, indicating that this action is not mediated via "high-affinity" benzodiazepine sites.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores de GABA-A
/
Moduladores GABAérgicos
/
Flavanonas
/
Ácido gama-Aminobutírico
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article