TY - JOUR
T1 - Prevention of physostigmine-, DFP-, and diazinon-induced acute toxicity by monoethylcholine and N-aminodeanol
AU - Patterson, T. A.
AU - Terry, A. V.
AU - Kosh, J. W.
PY - 1989
Y1 - 1989
N2 - 1. Choline, and the choline analogues monoethylcholine (MEC) and N-aminodeanol (NAD) were examined for prophylactic activity in acute acetylcholinesterase inhibitor toxicity in mice. The rank order of potency of the compounds was MEC > NAD > choline. 2. Simultaneous administration of MEC (60 mg kg-1) or NAD (200 mg kg-1) with physostigmine reduced lethality to 17 and 13% respectively. MEC (60 mg kg-1) completely protected against diisopropylfluorophosphate (DFP) and diazinin toxicity, and NAD reduced lethality to 17% for both agents. Choline (200 mg kg-1) exhibited only negligible antidotal activity against the inhibitors. 3. In vitro concentrations of choline, MEC, and NAD, similar to the estimated concentration obtained in vivo in the acute toxicity study, produced mixed inhibition of mouse brain acetylcholinesterase. The inhibition was dose-related and was additive to the inhibition produced by the cholinesterase inhibitors. 4. All three analogues reduced ligand binding at the nicotinic, M1, and M2 receptors. The rank order of potencies for the analogues at each receptor was nicotinic: (choline > MEC > NAD), M1: (MEC > choline > NAD), and M2: (MEC > choline > NAD). 5. It is proposed that the analogues prevent acetylcholinesterase inhibitor toxicity peripherally by interacting with acetylcholinesterase, and/or by competing with acetylcholine for binding to cholinoceptors.
AB - 1. Choline, and the choline analogues monoethylcholine (MEC) and N-aminodeanol (NAD) were examined for prophylactic activity in acute acetylcholinesterase inhibitor toxicity in mice. The rank order of potency of the compounds was MEC > NAD > choline. 2. Simultaneous administration of MEC (60 mg kg-1) or NAD (200 mg kg-1) with physostigmine reduced lethality to 17 and 13% respectively. MEC (60 mg kg-1) completely protected against diisopropylfluorophosphate (DFP) and diazinin toxicity, and NAD reduced lethality to 17% for both agents. Choline (200 mg kg-1) exhibited only negligible antidotal activity against the inhibitors. 3. In vitro concentrations of choline, MEC, and NAD, similar to the estimated concentration obtained in vivo in the acute toxicity study, produced mixed inhibition of mouse brain acetylcholinesterase. The inhibition was dose-related and was additive to the inhibition produced by the cholinesterase inhibitors. 4. All three analogues reduced ligand binding at the nicotinic, M1, and M2 receptors. The rank order of potencies for the analogues at each receptor was nicotinic: (choline > MEC > NAD), M1: (MEC > choline > NAD), and M2: (MEC > choline > NAD). 5. It is proposed that the analogues prevent acetylcholinesterase inhibitor toxicity peripherally by interacting with acetylcholinesterase, and/or by competing with acetylcholine for binding to cholinoceptors.
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U2 - 10.1111/j.1476-5381.1989.tb11972.x
DO - 10.1111/j.1476-5381.1989.tb11972.x
M3 - Article
C2 - 2569343
AN - SCOPUS:0024412420
SN - 0007-1188
VL - 97
SP - 451
EP - 460
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 2
ER -