The interaction of bis-pyridinium oximes with mouse brain muscarinic receptor

The bispyridinium oximes toxogonin [N, N′-oxydimethylene bis (pyridinium 4-aldoxim) dichloride] and its structural analogs HS-3, HS-6, HI-6 and MMB-4, and the bispyridinium salt SAD-128, which serve as antidotes to certain types of organophosphorus poisoning, bind competitively to mouse brain muscarinic receptors. This was determined in vitro employing the potent and specific muscarinic antagonist ³H-4NMPB (³H-4-N-methyl piperidyl benzilate). All the bispyridinium compounds also exerted a mild anti-acetylcholine activity (K_d = 10^-4-10^-5M) measured physiologically in the guinea pig ileum, which correlated well with the dissociation constants obtained from binding studies with mouse brain homogenate. The most potent muscarinic blocker was SAD-128 (K′_d = (7.1 ± 1.2) × 10^-6M for whole mouse brain), whose remarkable therapeutic action against soman intoxication may be partly attributed to this antimuscarinic activity. The binding data are best fitted by a competitive model, and the deviation from the law of mass action observed here may be related either to the heterogeneity of muscarinic receptors in the mouse brain or to nonequivalency of the number of binding sites for bisquaternary pyridines and 4-NMPB.