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

• Published in: Neuropharmacology 2007-09, Vol.53 (4), p.574-582
• Main Authors: Wang, Feng, Xu, Zhiwen, Yuen, Chun Tak, Chow, Chui Yin, Lui, Yuk Long, Tsang, Shui Ying, Xue, Hong
• Format: Article
• Language: English
• Subjects: Animals; Avoidance Learning - drug effects; Avoidance Learning - physiology; Binding, Competitive; Cell Line, Tumor; Flavones - pharmacology; Flavonoids - pharmacology; GABA Agonists - pharmacology; GABA-A Receptor Agonists; gamma-Aminobutyric Acid - metabolism; Humans; Male; Mice; Mice, Inbred ICR; Neuroblastoma; Patch-Clamp Techniques; Receptors, GABA-A - drug effects; Receptors, GABA-A - physiology
• ISSN: 0028-3908
• DOI: 10.1016/j.neuropharm.2007.06.018

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.