QSAR for acetylcholinesterase inhibition and toxicity of two classes of phosphoramidothioates

Methamidophos (Met) is a weak inhibitor of housefly head AChE but at the sa me time it is highly toxic to the common housefly. The lethality of Met is believed to be due to AChE inhibition. An extensive OSAR study may help in determining the mode of action of Met in vivo and in vitro and provide a ra tional for its high insecticidal toxicity. Acephate (Ace), like Met, is a p oor inhibitor of AChE in vitro and has a comparable to Met insect toxicity in vivo. Contrary to Met, though, Ace has much lower mammalian toxicity. Un derstanding the structural properties which make insecticides toxic to inse cts but not to mammals is of great importance, since mammals (including hum ans) are inadvertently exposed to these compounds. Our results were consistent with the model in which both the in vitro and i n vivo toxicity of Met depends on the inhibition of the active center of AC hE by the unchanged Met. An optimal susceptibility to hydrolysis is needed for Met and its analogs to have high insecticidal activity since in order t o phosphorylate AChE they need to be hydrolyzed and at the same time their stability is of great importance in vivo for accumulating at the site of ac tion. The insecticidal activity of Ace analogs may be due to direct interac tion with the active center of the AChE. The mammalian toxicity of Ace anal ogs may be due to interaction with an 'allosteric' reaction center in the A ChE.