Pharmacological studies on synthetic flavonoids: comparison with diazepam.
The present experiments compared the central BZ-omega binding characteristics and pharmacological profiles of two synthetic flavonoids (6-bromoflavone and 6-bromo-3'-nitroflavone) with those of the benzodiazepine (BZ) diazepam. In vitro experiments showed that while diazepam displaced [3H]flumazenil binding to the GABA(A) receptor in membranes from rat cerebellum and spinal cord, two brain areas enriched in the BZ-omega1 and BZ-omega2 receptor subtypes, with nearly equivalent half maximally effective concentrations, 6-bromo-3'-nitroflavone was somewhat more potent in displacing [3H]flumazenil binding to membranes from rat cerebellum (IC50 = 31 nM) than from spinal cord (IC50 = 120 nM), indicating selectivity for the BZ-omega1 receptor subtype. 6-Bromoflavone displayed weak (IC50 = 970 nM) affinity for the BZ-omega1 and no affinity for the BZ-omega2 (IC50 > 1000 nM) receptor subtypes. Diazepam, but not the synthetic flavonoids increased the latency to clonic seizures produced by isoniazid, thereby indicating that neither 6-bromoflavone nor 6-bromo-3'-nitroflavone display detectable intrinsic activity at GABA(A) receptors in vivo. Results from two conflict tests in rats showed that 6-bromoflavone (3-10 mg/kg) and 6-bromo-3'-nitroflavone (0.3-1 mg/kg) elicited anxiolytic-like activity in the punished drinking test, while both drugs were inactive in the punished lever pressing test. The positive effects displayed by the synthetic flavonoids in the punished drinking procedure were smaller than that of diazepam and were not antagonized by the BZ receptor antagonist flumazenil. In two models of exploratory activity, 6-bromoflavone (3-30 mg/kg) and 6-bromo-3'-nitroflavone (0.3-1 mg/kg) produced anxiolytic-like effects in the rat elevated plus-maze test, whereas both compounds failed to modify the behavior of mice in the light/dark test over a wide dose-range. The effects in the elevated plus-maze were antagonized by flumazenil. In the mouse defense test battery, where mice were confronted with a natural threat (a rat), 6-bromoflavone and 6-bromo-3'-nitroflavone failed to decrease flight reactions after the rat was introduced into the test area and risk assessment behavior displayed when subjects were constrained in a straight alley, and only weakly affected risk assessment of mice chased by the rat and defensive biting upon forced contact with the threat stimulus. In a drug discrimination experiment 6-bromoflavone and 6-bromo-3'-nitroflavone up to 30 and 3 mg/kg, respectively, did not substitute for the BZ chlordiazepoxide. Taken together, these results failed to demonstrate that the synthetic flavonoids 6-bromoflavone and 6-bromo-3'-nitroflavone possess anxiolytic-like properties similar or superior to that of diazepam, as was suggested previously. Furthermore, they question the contribution of BZ-omega receptors to the behavioral effects of 6-bromoflavone and 6-bromo-3'-nitroflavone.
Griebel
G
G
CNS Research Department, Synthélabo Recherche, Bagneux, France. ggriebel@compuserve.com
Perrault
G
G
Tan
S
S
Schoemaker
H
H
Sanger
D J
DJ
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001362:Avoidance Learning / Q000187:drug effects; D003975:Diazepam / Q000494:pharmacology* / Q000627:therapeutic use; D004193:Discrimination Learning / Q000187:drug effects; D004924:Escape Reaction / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use; D007538:Isoniazid; D008027:Light; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D011678:Punishment; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D018570:Risk Assessment; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control
C115897:6-bromo-3'-nitroflavone; C099934:6-bromoflavone; D014151:Anti-Anxiety Agents; D005419:Flavonoids; D011963:Receptors, GABA-A; D003975:Diazepam; D007538:Isoniazid