Pyridinium salts as organophosphate antagonists.

By a standard screening in vivo, a series of pyridinium salts were tested for their protective activity against organophosphate poisoning. In order to obtain information about the protective mechanisms, several biochemical properties of these compounds were investigated in vitro, viz., their influence upon the enzymes cholineacetyltransferase and acetylcholinesterase (AChE), reactivation and aging of phosphylated AChE, protection of AChE against phosphylation and their 'direct reaction' with the phosphylating agent. Both in vitro and in vivo several significant structure-activity relationships exist, which in some cases can be correlated, thus allowing an interpretation of the in vivo results on a biochemical basis. Thus the reactivating potency of bispyridinium-4-aldoximes towards diethylphosphoryl-AChE correlates well with the corresponding in vivo results when these compounds are used as antidotes against paraoxon poisoning. In the case of a treatment of soman poisoning the vivo results with a homologous series of oxime-free bispyridinium salts shows a reasonably good correlation with their protective action in vitro. The protective mechanisms of bifunctional bispyridinium monooximes remain uncertain. Several approaches to clarifying this question are discussed in detail.