6,3'-Dinitroflavone is a low efficacy modulator of GABAA receptors

R. FURTMUELLER; B. FURTMUELLER; A. C. PALADINI; C. WASOWSKI; M. MARDER; S. HUCK; W. SIEGHART

EUROPEAN JOURNAL OF PHARMACOLOGY

Elsevier

Año: 2008 vol. 591 p. 142 - 146

0014-2999

6,3´-Dinitroflavone 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 which is a specific antagonist at the benzodiazepine binding site of GABAA receptors we investigated the interaction of 6,3´-dinitroflavone with several recombinant GABAA receptor subtypes. Inhibition of [3H]flunitrazepam binding to recombinant GABAA receptors in transiently transfected HEK293 cells indicated that 6,3´-dinitroflavone exhibited the highest affinity for GABAA receptors composed of a1b2g2 subunits and a 5-20 fold lower affinity for homologous receptors containing a2, a3, or a5 subunits. Two electrode voltage clamp experiments in Xenopus oocytes indicated that 6,3´-dinitroflavone does not induce chloride flux in the absence of GABA, but exerts low efficacy inverse agonistic modulatory effects on GABA elicited currents in the GABAA receptor subtypes a1b2g2 and a5b2g2. In the subtypes a2b2g2, a3b2g2, a4b2g2, a6b2g2 or a4b2d and a4b3d, 6,3´-dinitroflavone exerts either none or very low efficacy positive modulatory effects. In contrast, 100nM 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´-dinitroflavone on a1b2g2 and a5b2g2 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´-dinitroflavone is discussed.