6-METHYLFLAVONE, A BENZODIAZEPINE RECEPTOR-LIGAND WITH ANTAGONISTIC PROPERTIES ON RAT-BRAIN AND HUMAN RECOMBINANT GABA(A) RECEPTORS IN-VITRO

Seventeen flavonoids were found to have inhibitory activity on the cen tral nervous system GABAA/benzodiazepine (BZD) receptors with IC50 val ues ranging from 0.12 to 8 mu M. 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 e xpressed in Sf-9 insect cells, as well as electrophysiologically by th e whole-cell patch clamp technique. Scatchard plot analysis showed tha t 6-methylflavone was a competitive inhibitor of [H-3]-Ro 15-1788, bin ding to rat brain cortical membranes. The GABA ratio of 1.06 for [H-3] -diazepam binding to cortex and 1.23 for cerebellum indicated an antag onistic or a weak partial agonistic profile of 6-methylflavone on the rat BZD(1) receptors, while the GABA ratio of 0.76 on hippocampus indi cated an antagonistic or partial-inverse agonistic profile on the BZD( 2) receptors. In Sf-9 insects cells, the GABA ratios showed a weak par tial agonistic profile on the alpha(1) beta(2) gamma(2S) (GABA ratio 1 .29) subtype combination, an antagonistic profile on the alpha(2) beta (2) gamma(2S) (1.13) and alpha(3) beta(2) gamma(2S) (1.03), and a part ial inverse agonistic profile on the alpha(5) beta(2) gamma(2S) (0.79) subtype combination. The modulation of GABA-induced chloride currents by 6-methylflavone suggests that the compound is an antagonist at hum an GABAA receptor subtypes. Based on our data of GABA(A)/BZD receptor active as well as inactive flavonoids, some general structure-activity relationships are discussed. (C) 1997 Wiley-Liss, Inc.