Benzodiazepine inhibition of [3H]flunitrazepam binding and caffeine-induced seizures in mice.
The median inhibitory and anticonvulsant potencies of seven benzodiazepine (BDZ) agonists and one BDZ antagonist (Ro15-1788) were established by two tests: inhibition of [3H]flunitrazepam receptor binding and prevention of caffeine-induced seizures in mice. The effect of Ro15-1788 on the anticonvulsant potency of diazepam against caffeine-induced seizures was also investigated. The [3H]flunitrazepam receptor binding inhibitory potencies (IC50s) of the BDZ agonists correlate well with their anticonvulsant potencies (ED50s) against caffeine-induced seizures (r = 0.831; P greater than 0.01 and less than 0.05). Ro15-1788 and clonazepam are the most potent inhibitors (IC50s: 1.72 and 1.75 nM, respectively), but differ markedly in their ability to obtund caffeine-induced seizures (ED50s: 43.2 and 0.226 mg/kg, respectively). Although both Ro15-1788 and diazepam are effective against caffeine-induced seizures, when used in combination Ro15-1788 antagonizes the anti-caffeine effect of diazepam. These data indicate that Ro15-1788 is a BDZ partial agonist with low efficacy as well as a potent antagonist.
Chweh
A Y
AY
Ulloque
R A
RA
Swinyard
E A
EA
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D002110:Caffeine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005442:Flumazenil; D005445:Flunitrazepam / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D011963:Receptors, GABA-A / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*
D014151:Anti-Anxiety Agents; D001570:Benzodiazepinones; D011963:Receptors, GABA-A; D002110:Caffeine; D005442:Flumazenil; D005445:Flunitrazepam