Document Detail

6,2'-Dihydroxyflavone, a subtype-selective partial inverse agonist of GABAA receptor benzodiazepine site.
MedLine Citation:
PMID:  17681556     Owner:  NLM     Status:  MEDLINE    
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.
Feng Wang; Zhiwen Xu; Chun Tak Yuen; Chui Yin Chow; Yuk Long Lui; Shui Ying Tsang; Hong Xue
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-06-30
Journal Detail:
Title:  Neuropharmacology     Volume:  53     ISSN:  0028-3908     ISO Abbreviation:  Neuropharmacology     Publication Date:  2007 Sep 
Date Detail:
Created Date:  2007-08-27     Completed Date:  2007-12-20     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0236217     Medline TA:  Neuropharmacology     Country:  England    
Other Details:
Languages:  eng     Pagination:  574-82     Citation Subset:  IM    
Department of Biochemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
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MeSH Terms
Avoidance Learning / drug effects,  physiology*
Binding, Competitive
Cell Line, Tumor
Flavones / pharmacology*
Flavonoids / pharmacology*
GABA Agonists / pharmacology*
Mice, Inbred ICR
Patch-Clamp Techniques
Receptors, GABA-A / agonists*,  drug effects,  physiology*
gamma-Aminobutyric Acid / metabolism
Reg. No./Substance:
0/6,2'-dihydroxyflavone; 0/Flavones; 0/Flavonoids; 0/GABA Agonists; 0/Receptors, GABA-A; 56-12-2/gamma-Aminobutyric Acid

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