6-Methylflavone, a benzodiazepine receptor ligand with antagonistic properties on rat brain and human recombinant GABA(A) receptors in vitro

Document Type

Article

Abstract

Seventeen flavonoids were found to have inhibitory activity on the central nervous system GABA(A)/benzodiazepine (BZD) receptors with IC 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 [ H]-Ro 15-1 788, binding to rat brain cortical membranes. The GABA ratio of 1.06 for [ 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 receptors, while the GABA ratio of 0.76 on hippocampus indicated an antagonistic or partial-inverse agonistic profile on the BZD receptors. In Sf-9 insects cells, the GABA ratios showed a weak partial agonistic profile on the α β γ(2S) (GABA ratio 1.29) subtype combination, an antagonistic profile on the α β γ(2S) (1.13) and α β γ(2S) (1.03), and a partial inverse agonistic profile on the α β 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. 50 1 2 1 2 2 2 3 2 5 2 3 3

Keywords

CNS, Electrophysiology, Flavonoids, GABA(A)/BZD receptor, Radioreceptor binding

Publication Date

6-1-1997

Publication Title

Drug Development Research

ISSN

02724391

Volume

41

Issue

2

First Page

99

Last Page

106

Digital Object Identifier (DOI)

10.1002/(SICI)1098-2299(199706)41:2<99::AID-DDR7>3.0.CO;2-M

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