6,2'-Dihydroxyflavone, a subtype-selective partial inverse agonist of GABAA receptor benzodiazepine site.

Abstract

Neuroactivity of a number of flavonoids is mediated by modulation of type A gamma-aminobutyric acid (GABA(A)) receptor function via benzodiazepine sites, mostly as partial agonists. In the present study, 6,2'-dihydroxyflavone (DHF) was characterized for potential inverse agonistic activity, and its mechanism of action was explored for receptor subtype selectivity. In whole-cell patch clamp studies on neuroblastoma IMR-32 cells expressing native GABA(A) receptors, DHF decreased GABA-induced currents, to an extent similar to that induced by the partial inverse agonist FG-7142, which could be blocked by flumazenil, a BZ site antagonist. In mouse behavioral models, DHF elicited significant anxiogenic-like effects in the elevated plus-maze test, and enhanced cognitive performance in the step-through passive avoidance test, as expected for an inverse agonist. However, DHF did not exhibit any proconvulsant effects, a typical action of inverse agonists. In electrophysiological studies on subtypes of recombinant GABA(A) receptors expressed in HEK 293T cells, DHF decreased GABA-induced currents in alpha(1)beta(3)gamma(2), alpha(2)beta(3)gamma(2), or alpha(5)beta(3)gamma(2), but not alpha(3)beta(3)gamma(2) receptors. The results demonstrated DHF as a partial inverse agonist-like modulator of GABA(A) receptors with selectivity in receptor subtypes as well as behavioral effects. The DHF subtype-selectivity suggested that alpha(3)-containing subtypes could be a mediator of the convulsion activities of GABA(A) receptor inverse agonists. Moreover, the pharmacological profile displayed in mouse behavioral models supported DHF as a useful lead compound for the development of cognition-enhancing agents devoid of convulsion side effects.

• Authors: Feng Wang, Zhiwen Xu, Chun Tak Yuen, Chui Yin Chow, Yuk Long Lui, Shui Ying Tsang, Hong Xue
• Journal: Neuropharmacology (Neuropharmacology) Vol. 53 Issue 4 Pg. 574-82 (Sep 2007) ISSN: 0028-3908 [Print] England
• PMID: 17681556 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 6,2'-dihydroxyflavone
• Flavones
• Flavonoids
• GABA Agonists
• GABA-A Receptor Agonists
• Receptors, GABA-A
• gamma-Aminobutyric Acid

Topics

• Animals
• Avoidance Learning (drug effects, physiology)
• Binding, Competitive
• Cell Line, Tumor
• Flavones (pharmacology)
• Flavonoids (pharmacology)
• GABA Agonists (pharmacology)
• GABA-A Receptor Agonists
• Humans
• Male
• Mice
• Mice, Inbred ICR
• Neuroblastoma
• Patch-Clamp Techniques
• Receptors, GABA-A (drug effects, physiology)
• gamma-Aminobutyric Acid (metabolism)