Interactions of pentamethylenetetrazole and tetrazole analogues with the picrotoxinin site of the benzodiazepine-GABA receptor-ionophore complex.

The interactions of pentamethylenetetrazole and ten tetrazole analogues with the picrotoxinin site of the benzodiazepine-GABA receptor-ionophore complex was investigated. All the active tetrazole analogues potently inhibited the binding of [35S]t-butyl- bicyclophosphorothionate ( TBPT ), a ligand which binds to the picrotoxinin site. Tetrazole analogues appear to interact with the picrotoxinin site competitively. All the tetrazole analogues tested were more potent in inhibiting TBPT binding than diazepam binding. There is a reasonably good correlation between the tetrazole analogues to inhibit TBPT binding and the doses at which they produce convulsions. Pentamethylenetetrazole inhibited TBPT binding at concentrations which are similar to the in vivo concentrations present during convulsions produced by this drug. These results suggest that tetrazoles may produce convulsions by acting at the picrotoxin-sensitive site of the benzodiazepine-GABA receptor-ionophore complex.