Binding characteristics and interactions of depressant drugs with [35S]t-butylbicyclophosphorothionate, a ligand that binds to the picrotoxinin site.
[35S]t-Butylbicyclophosphorothionate (TBPT), a cage convulsant with picrotoxinin-like activity, binds to rat brain membranes to a single site with an apparent KD of 25.1 +/- 5.6 nM and a Bmax of 1.40 +/- 0.22 pmol/mg protein. TBPT binding to rat brain membranes was inhibited by a variety of convulsant, depressant, anxiolytic, and anticonvulsant drugs that had previously been shown to inhibit [3H]alpha-dihydropicrotoxinin binding. Depressant drugs such as pentobarbital and the nonbarbiturate (+)etomidate inhibited TBPT binding in an uncompetitive manner. Thus, pentobarbital and (+)etomidate decreased both the affinity and the number of binding sites of TBPT to whole brain membranes. The IC50 values of (+)etomidate (9 microM) and pentobarbital (90 microM) are similar to the EC50 values at which they enhance both [3H]gamma-aminobutyric acid and [3H]diazepam binding in cerebral cortex membranes. RO5-4864, which has recently been shown to be a convulsant, also inhibited TBPT binding (IC50 = 10 microM). These results suggest that TBPT binds to the picrotoxinin site and further supports the notion that the picrotoxinin site is an important modulatory site at the benzodiazepine-GABA receptor-ionophore complex.
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001643:Bridged Bicyclo Compounds / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds / Q000378:metabolism*; D003292:Convulsants / Q000494:pharmacology*; D003975:Diazepam / Q000378:metabolism; D005045:Etomidate / Q000378:metabolism; D008297:Male; D008566:Membranes / Q000378:metabolism; D010424:Pentobarbital / Q000378:metabolism; D010852:Picrotoxin / Q000031:analogs & derivatives* / Q000378:metabolism; D011619:Psychotropic Drugs / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D054830:Sesterterpenes; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds; D003292:Convulsants; D003975:Diazepam; D005045:Etomidate; D010424:Pentobarbital; D010852:Picrotoxin; D011619:Psychotropic Drugs; D054830:Sesterterpenes; D005680:gamma-Aminobutyric Acid; C037476:tert-butylbicyclophosphorothionate; C022961:picrotoxinin