6,2'-Dihydroxyflavone, a subtype-selective partial inverse agonist of GABAA receptor benzodiazepine site.
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.
Wang
Feng
F
Department of Biochemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
Xu
Zhiwen
Z
Yuen
Chun Tak
CT
Chow
Chui Yin
CY
Lui
Yuk Long
YL
Tsang
Shui Ying
SY
Xue
Hong
H
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D047309:Flavones / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009447:Neuroblastoma; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C525012:6,2'-dihydroxyflavone; D047309:Flavones; D005419:Flavonoids; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid