1. The pharmacological properties of the
benzodiazepine receptor ligand,
FG 8205 (7-chloro-5,6-dihydro-5-methyl-6-oxo-3-(5-isopropyl-1,2,4-oxadiazol++ +-3-yl)-4H- imidazol[1,5a][1,4]
benzodiazepine) have been examined. 2.
FG 8205 potently displaced [3H]-
flumazenil binding in rat cortical membranes with a Ki of 3.3 nM, but was inactive at 13
neurotransmitter recognition sites. 3. Consistent with a partial agonist profile, the affinity of
FG 8205 for the
benzodiazepine recognition site was increased in the presence of
gamma-aminobutyric acid (
GABA, 300 microM) by a degree (-log [IC50 in the presence of
GABA/IC50 alone] = 0.34) significantly less than found for
diazepam (0.46).
FG 8205 also potentiated the inhibitory potency of the GABAA-receptor agonist,
isoguvacine, on the hippocampal CA1 population spike and, again, the maximum shift (-log dose-ratio = 0.2) was significantly less than that seen with
diazepam (0.4). 4. In
anticonvulsant studies, the ED50 doses of
FG 8205 and
diazepam needed to antagonize
seizures induced by
pentylenetetrazol (PTZ) or by sound in audiogenic seizure prone mice were similar with values of 0.2-0.3 mg kg-1, i.p. However, even high doses of
FG 8205 (50 mg kg-1) did not protect against
seizures induced by electroshock. 5.
FG 8205 released responding suppressed by footshock in a rat operant conditioned emotional response task over the dose range 0.5-50 mg kg-1 (i.p.). Similar doses of
FG 8205 had a marked taming effect in cynomolgus monkeys. However, measures of sedation and
ataxia (as measured by rotarod in the mouse, climbing behaviour in the rat, and by scoring arousal and co-ordination in primates) were slight and only transiently affected by
FG 8205, and
FG 8205 significantly antagonized the rotarod performance deficit induced by
diazepam in the mouse. 6. While the potentiation by
FG 8205 of the response to
isoguvacine in the rat hippocampal slice and the
anxiolytic-like effects of the compound in both rats and primates were reversed by the
benzodiazepine receptor antagonist,
flumazenil, high doses of the antagonist were able only marginally to block the protective effects of
FG 8205 against
seizures induced by PTZ in the mouse. 7. Thus,
FG 8205 does not show the marked motor impairment characteristic of full agonists at the
benzodiazepine receptor, consistent with its partial agonist profile in in vitro assay systems. Nevertheless, the compound has sufficient intrinsic activity to maintain high efficacy in
anticonvulsant and
anxiolytic tests.