6-Methylflavone, a benzodiazepine receptor ligand with antagonistic properties on rat brain and human recombinant GABAA receptors in vitro
✍ Scribed by Jinglu Ai; Kim Dekermendjian; Xiaomei Wang; Mogens Nielsen; Michael-Robin Witt
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- English
- Weight
- 157 KB
- Volume
- 41
- Category
- Article
- ISSN
- 0272-4391
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✦ Synopsis
Seventeen flavonoids were found to have inhibitory activity on the central nervous system GABA A /benzodiazepine (BZD) receptors with IC 50 values ranging from 0.12 to 8 µM. 6-Methylflavone, the most potent, was pharmacologically characterized by radioligand binding assays on rat brain membranes in vitro and human recombinant GABA A /BZD receptors expressed in Sf-9 insect cells, as well as electrophysiologically by the whole-cell patch clamp technique. Scatchard plot analysis showed that 6-methylflavone was a competitive inhibitor of [ 3 H]-Ro 15-1788, binding to rat brain cortical membranes. The GABA ratio of 1.06 for [ 3 H]-diazepam binding to cortex and 1.23 for cerebellum indicated an antagonistic or a weak partial agonistic profile of 6-methylflavone on the rat BZD 1 receptors, while the GABA ratio of 0.76 on hippocampus indicated an antagonistic or partial-inverse agonistic profile on the BZD 2 receptors. In Sf-9 insects cells, the GABA ratios showed a weak partial agonistic profile on the α 1 β 2 γ 2S (GABA ratio 1.29) subtype combination, an antagonistic profile on the α 2 β 2 γ 2S (1.13) and α 3 β 2 γ 2S (1.03), and a partial inverse agonistic profile on the α 5 β 2 γ 2S (0.79) subtype combination. The modulation of GABA-induced chloride currents by 6-methylflavone suggests that the compound is an antagonist at human GABA A receptor subtypes. Based on our data of GABA A /BZD receptor active as well as inactive flavonoids, some general structure-activity relationships are discussed.