Add time:08/25/2019         Source:sciencedirect.com

The potent dihydropyrazole insecticide RH 3421 (methyl 1-(N-(α,α,α,-trifluoro-p-tolyl)carbamoyl-3-(4-chlorophenyl)-4-methyl-2-pyrazolin-4-ylcarboxylate), which has previously been shown to block voltage-gated and neurotoxin-activated sodium currents through sodium channels in insect nerves and insect and mammalian synaptic vesicles, inhibited the binding of [3H]batrachotoxinin A 20-α-benzoate (BTX-B) to the alkaloid activator recognition site (Site 2) of voltage-sensitive sodium channels in mouse brain preparations. The presence of veratridine or a high concentration of BTX-B reduced the potency of RH 3421 as an inhibitor of BTX-B binding, but a concentration of RH 3421 close to its I50 value did not alter the inhibitory potency of veratridine. Equilibrium saturation studies showed that RH 3421 at 0.2 μM acted as a noncompetitive inhibitor of BTX-B binding, decreasing the apparent density of BTX-B binding sites in mouse brain vesicles by approximately 40% without affecting the affinity of mouse brain sodium channels for this ligand. Kinetic experiments showed that RH 3421 at 0.2 μM had no effect on the rates of association or dissociation of BTX-B, but RH 3421 at 10 μM increased the dissociation rate approximately threefold. Preincubation of vesicles with RH 3421 followed by repeated washing and resuspension produced a progressive recovery of specific BTX-B binding, thereby demonstrating that the binding of RH 3421 to sodium channels was slowly reversible. These results show that RH 3421 binds to a site on the voltage-sensitive sodium channel that is allosterically coupled to Site 2, the activator recognition site, and acts as a noncompetitive inhibitor of the binding of Site 2 ligands. The dihydropyrazole recognition site exhibits properties similar to the binding site(s) for local anesthetics, class I anticonvulsants, and class I antiarrhythmics on the sodium channel.

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