title: RO5-4864 inhibits the binding of [35S]t-butylbicyclophosphorothionate to rat brain membranes.
abstract: RO5-4864, a 1,4-benzodiazepine, has recently been shown to possess anticonvulsant, convulsant and anxiogenic properties and to inhibit Ca++-calmodulin-stimulated membrane phosphorylation. RO5-4864 inhibited the binding of [35S]t-butylbicyclophosphorothionate (TBPT) to cerebral cortex, cerebellar and hippocampus membranes, with an IC50 value of approximately 20 microM. TBPT binds apparently to the picrotoxinin site of the benzodiazepine-GABA receptor-ionophore complex and appears to be a site of action for several classes of convulsant, depressant and anxiolytic drugs that modulate GABAergic transmission. RO5-4864 inhibited [35S] TBPT binding in cerebral cortex, apparently competitively. Antagonists of GABA and central benzodiazepine sites did not interfere with the ability of RO5-4864 to inhibit [35S] TBPT binding. The properties of RO5-4864 to inhibit TBPT binding are similar to other convulsants and GABA antagonists (except bicuculline) which inhibit TBPT binding. These results suggest that RO5-4864 interacts with the TBPT binding sites of the oligomeric GABA receptor complex.
mesh_terms: D000731:Androstanes / Q000494:pharmacology; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology; D001570:Benzodiazepinones / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001643:Bridged Bicyclo Compounds / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds / Q000378:metabolism*; D002243:Carbolines / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D010852:Picrotoxin / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats
chemical_list: D000731:Androstanes; D001378:Azasteroids; D001570:Benzodiazepinones; D001640:Bicuculline; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds; D002243:Carbolines; D005442:Flumazenil; D010852:Picrotoxin; C028513:4'-chlorodiazepam; C037476:tert-butylbicyclophosphorothionate; C024915:beta-carboline-3-carboxylic acid ethyl ester; C032061:RU 5135