Comparison of Bicyclophosphate Binding to the Putative Chloride Channels in Rat Brain and Torpedo Electric Organ

摘要

Trioxabicyclooctanes of the structure X-P (OCH2)3C-Y represent a class of potent convulsants that are believed to antagonize GABA neurotransmission by blocking the conductance of anions through the C1-channel. We compare the relative potency and C1 - channel binding specificity of several bicyclophosphate derivatives in membrane preparations derived from the Torpedo electric organ and rat brain. Membranes were labeled with 35S-t-butylbicyclophosphorothionate (35S-TBPS), and the concentration of each test compound required to produce 50% inhibition (IC50) of radioligand binding was determined. The hexachlorocyclohexane insecticide, lindane, proved 10 times more potent in displacing 35S-TBPS from electric organ than rat brain, whereas the bicyclophosphate analogs displayed up to 3 orders of magnitude greater affinity for rat brain over electric organ. Lindane also showed moderate affinity for the Na+ channel in electric organ. GABA inhibited 35S-TBPS binding with moderate potency, whereas unlabeled TBPS inhibited GABA receptor binding at concentrations greater than 100 micromoles. The GABA receptor antagonist bicuculline both reversed and potentiated 35S-TBPS binding in the presence of 10 micromoles GABA. We conclude that lindane and TBPS are the most potent of the compounds examined, whereas the i-propyl phosphate derivative (X=O, Y=C3H7) is the most selective compound for discriminating between voltage-sensitive (electric organ) and chemically-gated (rat brain) C1 - channel binding sites.