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 greater than NAD greater than 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 disopropylfluorophosphate (DFP) and diazinon 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 greater than MEC greater than NAD), M1: (MEC greater than choline greater than NAD), and M2: (MEC greater than choline greater than 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.
Patterson
T A
TA
Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia 29208.
Terry
A V
AV
Kosh
J W
JW
D000818:Animals; D002794:Choline / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D002801:Cholinesterase Reactivators; D003976:Diazinon / Q000037:antagonists & inhibitors* / Q000633:toxicity; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D010830:Physostigmine / Q000037:antagonists & inhibitors* / Q000633:toxicity; D011759:Pyrrolidines / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000378:metabolism
D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D018377:Neurotransmitter Agents; D011759:Pyrrolidines; D011950:Receptors, Cholinergic; C007268:1-(2-(dodecyloxy)ethyl)pyrrolidine hydrochloride; C038146:N-amino-N,N-dimethylaminoethanol; C024769:monoethylcholine; D010830:Physostigmine; D002794:Choline; D003976:Diazinon