In vitro and in vivo protection of acetylcholinesterase against organophosphate poisoning by pretreatment with a novel derivative of 1,3,2-dioxaphosphorinane 2-oxide

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Abstract
Covalent molecular combinations of a cyclic phosphate (dioxaphosphorinane) and a potential leaving group, such as 3-(trimethylammonio)phenol iodide (TMPH), suggested the synthesis of O-[3-(trimethylammonio)phenyl]-1,3,2-dioxaphosphorinane 2-oxide iodide (TDPI). TDPI inhibited acetylcholinesterase (AChE) (ki [inhibition constant] = 8.4 .times. 103 M-1 min-1) via the formation of an unstable covalent intermediate. TDPI-inhibited AChE hydrolyzed spontaneously with t1/2 [half-life] .apprxeq. 10 min. Butyrylcholinesterase (BuChE) was inhibited by TDPI (ki = 1.8 .times. 104 M-1 min-1), but the inhibited BuChE was more stable (> 10 times) than the corresponding AChE-TDPI conjugate. Pretreatment of mice with TDPI conferred protection against 22 LD50 and 5 LD50 of paraoxon and 5 LD50 of soman, provided that treatment with anticholinergics and an oxime followed administration of these anticholinesterase poisons. Correlation between in vitro and in vivo observations suggests that the main protection of AChE conferred by TDPI results from temporary masking of the active site of the enzyme. The acute toxicity of TDPI was 444 mg/kg (s.c. mice), whereas masking of the active site of the enzyme. The acute toxicity of TDPI was 444 mg/kg (s.c. mice), whereas analogous carbamates and a noncyclic phosphate displaying antidotal properties are > 170 times more toxic.