title: The pharmacological properties of the imidazobenzodiazepine, FG 8205, a novel partial agonist at the benzodiazepine receptor.
abstract: 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.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex.
authors.forename: M D
authors.initials: MD
authors.lastname: Tricklebank
authors.forename: T
authors.initials: T
authors.lastname: Honoré
authors.forename: S D
authors.initials: SD
authors.lastname: Iversen
authors.forename: J A
authors.initials: JA
authors.lastname: Kemp
authors.forename: A R
authors.initials: AR
authors.lastname: Knight
authors.forename: G R
authors.initials: GR
authors.lastname: Marshall
authors.forename: N M
authors.initials: NM
authors.lastname: Rupniak
authors.forename: L
authors.initials: L
authors.lastname: Singh
authors.forename: S
authors.initials: S
authors.lastname: Tye
authors.forename: F
authors.initials: F
authors.lastname: Watjen
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines; D001570:Benzodiazepinones / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000502:physiology; D003213:Conditioning, Psychological / Q000187:drug effects; D003975:Diazepam / Q000494:pharmacology; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D012640:Seizures / Q000517:prevention & control
chemical_list: D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D001570:Benzodiazepinones; D011963:Receptors, GABA-A; C063822:L 663581; D001569:Benzodiazepines; D003975:Diazepam