The delayed neuropathic effects of nerve agents and some other organophosphorus compounds

Abstract

The in vitro inhibitory potencies of several nerve agents and other organophosphorus compounds against acetylcholinesterase (AChE) and neurotoxic esterase (NTE) have been compared. Although the I₅₀s against AChE were about 0.1–1.0 nM for the nerve agents the I₅₀s against NTE for sarin, soman and tabun were two to four orders of magnitude higher and VX had negligible activity. A series of bis[(ω-phenyl-n-alkyl]phosphorofluoridates inhibited both enzymes at 1.0–100 nM while ω-phenyl-n-alkyl NN-dimethylphosphoramidofluoridates were active at 0.1–10 μM. From the in vitro data it was predicted that nerve agents would cause delayed neuropathy only at doses greatly exceeding the LD₅₀. In hens protected against acute toxicity by pretreatment with physostigmine, atropine and the oxime P2S, delayed neuropathy associated with high inhibition of NTE was found at 30–60 × LD₅₀ for sarin but not at 38 × LD₅₀ for soman or 82 × LD₅₀ for tabun. At the maximum doses tested of the latter two compounds the inhibition of NTE was 55% and 66% respectively. The minimum neuropathic doses were calculated to be about 100–150 × LD₅₀ for soman and tabun.

As expected from in vitro data, neuropathy, associated with a high level of inhibition of NTE, was caused by one of the bis-phenylalkyl phosphorofluoridates at doses causing negligible acute toxicity. The required dose was 9X that for DFP although the compound was 300X more active against NTE in vitro suggesting that such compounds are rapidly degraded in vivo. The phenylalkyl NN-dimethylphosphoramidofluoridates produced prolonged acute signs of poisoning but they were not neuropathic at the maximum tolerable doses nor was the NTE greatly inhibited contrary to the prediction from the in vitro data. It is possible that the enantiomer responsible for the inhibition of NTE is preferentially degraded in vivo.

Several other phosphoramidofluoridates inhibit NTE in vitro at 1.0–100 μM and a number of bicyclic phosphates were inactive at 23 μM. None of these compounds was tested in vivo.