Prevention of physostigmine-, DFP-, and diazinon-induced acute toxicity by monoethylcholine and N-aminodeanol

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.