A powerful reactivator of alkylphosphate-inhibited acetylcholinesterase

Wilson, Irwin B.; Ginsburg, Benson E.

doi:10.1016/0006-3002(55)90040-8

Cited by 473 publications

(159 citation statements)

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“…It has recently been found that relatively small amounts of certain oximes speedily restore the activity of freshly phosphorylated true cholinesterases in vitro (Childs et al, 1955;Wilson and Ginsburg, 1955). The results presented in this paper show that in the mouse pyridine-2-aldoxime methiodide (P-2-AM), which was the most active oxime found so far, was less effective in reactivating phosphorylated true cholinesterases in vivo than was indicated by the in vitro experiments.…”

Section: Discussionmentioning

confidence: 66%

“…Reactivation of phosphorylated cholinesterase in aqueous solution is determined by the dialkylphosphoryl group and can be markedly enhanced in vitro by nucleophilic reagents which remove the dialkylphosphoryl group from the enzyme by virtue of their high affinity for the phosphorus. One of the most powerful reactivators of phosphorylated true cholinesterase is pyridine-2-aldoxime methiodide (P-2-AM) (Childs, Davies, Green, and Rutland, 1955;Wilson and Ginsburg, 1955). The concentrations of P-2-AM which are required to restore 50% of the activity of phosphorylated human true cholinesterase within 1 hr.…”

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confidence: 99%

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Protection Against the Lethal Effects of Organo‐phosphates by Pyridine‐2‐aldoxime Methiodide

Hobbiger

1957

British Journal of Pharmacology and Chemotherapy

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The mechanism responsible for the protection against lethal organophosphate poisoning by pyridine-2-aldoxime methiodide (P-2-AM) was studied in the mouse. Two types of organophosphates were used: ethyl pyrophosphate (TEPP), E 600, Ro 3-0340, and Ro 3-0422 which form with true cholinesterase a diethylphosphoryl enzyme (1) and DFP, D 600, and Ro 3-0351 which form with true cholinesterase a diisopropylphosphoryl enzyme (2).In vitro and under the experimental conditions used more than 50% reactivation of (1) was obtained within 1 hr. by concentrations of P-2-AM ranging from 0.5 to 1 x I0D-M; 30 times higher concentrations of the oxime were required to achieve the same effect with (2). In vivo reactivation of phosphorylated true cholinesterases in blood amounted to 10 to 24% within the first 30 min. if 25 mg./kg. P-2-AM was injected (i.p.) 5 min. before a sublethal dose of TEPP, E 600, Ro 3-0340, or Ro 3-0422 and reactivation reached a maximum within I to 2 hr. after the injection of the oxime. P-2-AM was more effective when given 30 min. after the organophosphate. The effect of 25 mg./kg. P-2-AM on the phosphorylated true cholinesterase in brain (experiments with TEPP and E 600) was negligible. A dose of 25 mg./kg. P-2-AM had no consistent effect on the phosphorylated true cholinesterases in blood and brain of mice injected with sublethal doses of DFP, D 600, or Ro 3-0351.The protection by 25 mg./kg. P-2-AM against lethal doses of TEPP, E 600, Ro 3-0422, and Ro 3-0340 was greater than that obtained with 50 mg./kg. atropine sulphate, but the degree of protection was determined by the organophosphate itself and not its dialkylphosphoryl group. Protection by 25 mg./kg. P-2-AM against lethal doses of DFP, D 600, and Ro 3-0351 was negligible. The antidotal effect of P-2-AM was potentiated by atropine. Mice which were injected with atropine and P-2-AM were protected to a greater extent against DFP than against Ro 3-0422, and protection against DFP was only slightly less than protection against TEPP. This is difficult to reconcile with a specific action of P-2-AM on phosphorylated cholinesterases.

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Section: Discussionmentioning

confidence: 66%

mentioning

confidence: 99%

Protection Against the Lethal Effects of Organo‐phosphates by Pyridine‐2‐aldoxime Methiodide

Hobbiger

1957

British Journal of Pharmacology and Chemotherapy

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“…When pralidoxime iodide was first proposed as an antidote for anticholinesterase poisoning (Wilson & Ginsburg, 1955;Childs, Davies, Green & Rutland, 1955), it appeared that its action was simply to reactivate alkyl phosphate-inhibited cholinesterase. It is now evident from the investigations of the last 6 years that this and other similar oximes have many actions.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of the Antagonism by Pralidoxime and 1,1‐trimethylenebis(4‐hydroxyiminomethylpyridinium) of the Action of Echothiophate on the Intestine

Lehman¹

1962

British Journal of Pharmacology and Chemotherapy

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Pralidoxime chloride (pyridine-2-aldoxime methochloride; Protopam Chloride) and 1,1'-trimethylenebis(4-hydroxyiminomethylpyridinium bromide) (TMB-4) antagonize the spasm of the isolated or intact small intestine of the rabbit caused by the anticholinesterase, echothiophate iodide (S-2-dimethylaminoethyl OO-diethyl phosphorothiolate methiodide; Phospholine Iodide). In vitro, both oximes also antagonize the spasm caused by acetylcholine. The quantitative relationships have been studied in comparison with the activity of atropine against echothiophate and acetylcholine. Echothiophate-treated intestine which is subjected to a concentration of oxime sufficient to cause 100% restoration of function (but not cholinesterase reactivation) will go back into spasm on washing out both drugs. Strips treated with a high concentration of oxime, sufficient to cause 100% reactivation of cholinesterase, exhibit normal control tone and motility after washing. It is concluded that pralidoxime and 1,1'-trimethylenebis(4-hydroxyiminomethylpyridinium bromide) have an anticholinergic action as well as the ability to reactivate cholinesterase and that this action plays a significant part in the initial recovery of function under the conditions of these experiments.

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“…Phosphorylated cholinesterases can be reactivated by specifically designed nucleophiles such as pyridine aldoxime methiodide (PAM) [15]. We added 5 mM PAM to AChE inhibited by HDEP and noticed a rapid restoration of enzymic activity which was complete in a few minutes.…”

Section: Reactivation Of Inhibited Cholinesterasesmentioning

confidence: 99%

Alkynyl phosphates are potent inhibitors of serine enzyme

Segal¹,

Shalitin²,

Shalitin³

et al. 1996

FEBS Letters

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Propynyl, hexynyl and t-butylethynyl diethyl phosphates were found to be very powerful covalent inhibitors of serine enzymes. Esterases were inhibited with second-order rate constants of 107-10 s M -I min -1. Most proteases were inhibited with a rate constant of 104-10 s M -r min -1. By inhibiting chymotrypsin with (3-14C)-l-propynyl diethyl phosphate, it was established that inhibition was caused by binding of the phosphate group to the enzyme active site.

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A powerful reactivator of alkylphosphate-inhibited acetylcholinesterase

Cited by 473 publications

References 2 publications

Protection Against the Lethal Effects of Organo‐phosphates by Pyridine‐2‐aldoxime Methiodide

Protection Against the Lethal Effects of Organo‐phosphates by Pyridine‐2‐aldoxime Methiodide

Mechanism of the Antagonism by Pralidoxime and 1,1‐trimethylenebis(4‐hydroxyiminomethylpyridinium) of the Action of Echothiophate on the Intestine

Alkynyl phosphates are potent inhibitors of serine enzyme

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