Prevention of organophosphate-induced toxicity in mice.
bis-Quaternary amines, which are acetal analogues of hemicholinium-3, were synthesized and several compounds were potent chemicals to antagonize toxicity induced by the organophosphate, paraoxon. Structural requirements were specific and included two oxygen atoms (bis-acetal substitution) within 6 or 7 atom heterocyclic rings, oxygen atoms spaced 2-carbon atoms from the quaternary nitrogen, and carbonyl substitutions adjacent to the spacing moieties, either bicyclohexyl or biphenyl. Biological testing showed a positive potency correlation between the chemicals when data from the following tests were compared: antagonism in mice of paraoxon-induced motor impairment using the incline screen and toxicity, and ability to induce contractions of guinea-pig isolated ilea. The compounds were compared with the often used protective antagonist of organophosphate-induced toxicity, pyridostigmine. One compound, MFS-3, was seven times more efficacious and possessed a much higher therapeutic index. Possible mechanisms of action for these chemicals are discussed.
Department of Pharmacology, College of Medicine, University of Iowa, Iowa City 52242, USA.
U
U
Ozkutlu
J P
JP
Long
J G
JG
Cannon
M F
MF
Sahin
C
C
Liang
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006426:Hemicholinium 3 / Q000031:analogs & derivatives*; D007082:Ileum / Q000187:drug effects*; D007306:Insecticides / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009469:Neuromuscular Junction / Q000187:drug effects*; D010261:Paraoxon / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011041:Poisoning / Q000517:prevention & control; D011729:Pyridostigmine Bromide / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D006426:Hemicholinium 3; D011729:Pyridostigmine Bromide; D010261:Paraoxon