The nonoxime bispyridinium compound SAD-128 alters the kinetic properties of the nicotinic acetylcholine receptor ion channel: a possible mechanism for antidotal effects.

The effects of SAD-128 [1,1'-oxybis(methylene) bis 4-(1,1-dimethylethyl) pyridinium dichloride], a nonoxime bispyridinium compound, were investigated on the nicotinic acetylcholine receptor-ion channels of frog muscle fibers using end-plate current (EPC) and single channel current measurement techniques. SAD-128 decreased the EPC peak amplitude in a concentration-dependent manner and caused nonlinearity in the current-voltage plots. The time constant of EPC decay was prolonged by SAD-128 (10-200 microM) at potentials between +50 and -90 mV without loss of the single exponential decay. However, at -100 mV and below, biphasic decays of the EPCs were observed in the presence of the drug. The time constant of the fast phase of the EPC decay decreased, whereas that of the slow phase increased, with either hyperpolarization or increasing concentration of the drug. SAD-128 weakly inhibited acetylcholinesterase in frog sartorius muscle. At the single-channel current level, SAD-128 reduced the mean channel open time and produced a blocked state evidenced as an additional phase in the closed time distribution. The agent induced a biphasic burst time distribution whose fast component became faster and slow component slower with increasing concentration and hyperpolarization. The present study provides more details regarding the kinetics of the nicotinic acetylcholine receptor ion channel-blocking mechanisms and a correlation between single-channel currents and macroscopic events. The ability of SAD-128 to block the nicotinic acetylcholine receptor may underlie its efficacy in counteracting lethal effect of organophosphorus compounds.