6-Chloro-3′-nitroflavone is a Potent Ligand for the Benzodiazepine Binding Site of the GABA A Receptor Devoid of Intrinsic Activity

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6-Chloro-3′-nitroflavone integrates a list of nearly 70 flavone derivatives synthesized in our laboratories. The effects of 6-chloro-3′-nitroflavone on the benzodiazepine binding sites (BDZ-BSs) of the GABA A receptor were examined in vitro and in vivo. 6-Chloro-3′-nitroflavone inhibited the [ 3H]flunitrazepam ([ 3H]FNZ) binding to rat cerebral cortex membranes with a K i of 6.68 nM and the addition of GABA to extensively washed membranes did not modify its affinity for the BDZ-BSs (GABA-shift = 1. 16 ± 0.12). The binding assays performed in rat striatal and cerebellar brain membranes showed that this compound has similar affinity to different populations of BDZ-BSs. Electrophysiological experiments revealed that 6-chloro-3′-nitroflavone did not affect GABA A-receptors (GABA A-Rs) responses recorded in Xenopus oocytes expressing α 1β 2γ 2s subunits, but blocked the potentiation exerted by diazepam (DZ) on GABA-activated chloride currents. In vivo experiments showed that 6-chloro-3′-nitroflavone did not possess anxiolytic, anticonvulsant, sedative, myorelaxant actions in mice or amnestic effects in rats; however, 6-chloro-3′-nitroflavone antagonized diazepam-induced antianxiety action, anticonvulsion, short-term, and long-term amnesia and motor incoordination. These biochemical, electrophysiological, and pharmacological results suggest that 6-chloro-3′-nitroflavone behaves as an antagonist of the BDZ-BSs.