Convulsant potencies of tetrazoles are highly correlated with actions on GABA/benzodiazepine/picrotoxin receptor complexes in brain.
A series of tetrazole convulsants were examined for their potencies in displacing [35S]-t-butylbicyclophosphorothionate (TBPS) from the picrotoxin site on the benzodiazepine-GABA-chloride ionophore receptor complex. All of the tetrazole derivatives tested inhibited [35S]-TBPS binding from rat forebrain membranes, and except for one (undecamethylenetetrazole), had Hill coefficients near unity. Similar to other chemically unrelated convulsants the inhibition of [35S]-TBPS binding by the various tetrazole derivatives was unaffected by the addition of the bicucculine-like GABA antagonist, R 5135. To ascertain whether the inhibition of specific [35S]-TBPS binding by the tetrazole derivatives was related to their convulsant properties, we compared their in vitro potencies in displacing [35S]-TBPS binding with their minimum convulsant potencies in mice. A very good correlation was observed (r = 0.96, p less than 0.001) between their relative affinities for the [35S]-TBPS binding site and their convulsant potencies, indicating that pentamethylenetetrazol and related tetrazoles may produce their convulsant and anxiogenic actions via the GABA-benzodiazepine-chloride ionophore receptor complex.
D000818:Animals; D001393:Azoles / Q000633:toxicity*; D001569:Benzodiazepines / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D003292:Convulsants; D046911:Macromolecular Substances; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000633:toxicity*
D001393:Azoles; D003292:Convulsants; D046911:Macromolecular Substances; D011963:Receptors, GABA-A; D013777:Tetrazoles; C037480:picrotoxinin receptor; D001569:Benzodiazepines