6,3'-Dinitroflavone is a low efficacy modulator of GABA(A) receptors

Eur J Pharmacol. 2008 Sep 4;591(1-3):142-6. doi: 10.1016/j.ejphar.2008.06.093. Epub 2008 Jul 2.

Abstract

6,3'-Dinitroflavone (6,3'-DNF) is a synthetic flavone derivative that exerts anxiolytic effects in the elevated plus maze. Based on the finding that this effect is blocked by Ro15-1788 (ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate) which is a specific antagonist at the benzodiazepine binding site of GABA(A) receptors we investigated the interaction of 6,3'-DNF with several recombinant GABA(A) receptor subtypes. Inhibition of [(3)H]flunitrazepam binding to recombinant GABA(A) receptors in transiently transfected HEK293 cells indicated that 6,3'-DNF exhibited the highest affinity for GABA(A) receptors composed of alpha1beta2gamma2 subunits and a 2-20 fold lower affinity for homologous receptors containing alpha2, alpha3, or alpha5 subunits. Two-electrode voltage-clamp experiments in Xenopus oocytes indicated that 6,3'-DNF does not induce chloride flux in the absence of GABA, but exerts low efficacy inverse agonistic modulatory effects on GABA-elicited currents in the GABA(A) receptor subtypes alpha1beta2gamma2 and alpha5beta2gamma2. In the subtypes alpha2beta2gamma2, alpha3beta2gamma2, alpha4beta2gamma2, alpha6beta2gamma2 or alpha4beta2delta and alpha4beta3delta, 6,3'-DNF exerts either none or very low efficacy positive modulatory effects. In contrast, 100 nM Ro15-1788 exhibited weak to moderate partial agonistic effects on each receptor investigated. These data indicate that Ro15-1788 only can antagonize the weak inverse agonist effects of 6,3'-DNF on alpha1beta2gamma2 and alpha5beta2gamma2 receptors, but will enhance the weak agonistic effects on the other receptor subtypes investigated. The possible mechanism of the Ro15-1788 sensitive anxiolytic effect of 6,3'-DNF is discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Anxiety Agents / metabolism*
  • Cell Line
  • Chlorides / metabolism
  • Female
  • Flavonoids / metabolism*
  • Flumazenil / pharmacology*
  • Flunitrazepam / metabolism
  • GABA Modulators / pharmacology
  • Humans
  • Oocytes
  • Patch-Clamp Techniques
  • Protein Binding
  • Protein Subunits / metabolism
  • Receptors, GABA-A / drug effects*
  • Receptors, GABA-A / metabolism
  • Transfection
  • Xenopus

Substances

  • Anti-Anxiety Agents
  • Chlorides
  • Flavonoids
  • GABA Modulators
  • Protein Subunits
  • Receptors, GABA-A
  • 3',6-dinitroflavone
  • Flumazenil
  • Flunitrazepam