Hemicholinium-3 congeners as potential antagonists to organophosphate-induced toxicity.
A series of congeners of hemicholinium-3, in which the 1,4-oxazinium rings of hemicholinium are replaced by pyrrolidine, piperidine, 1,3-dioxane, or 1,4-oxazine rings, is described. Several of the target compounds produced blockade of neuromuscular transmission in the rabbit, and three heterocyclic derivatives, 10, 11, and 13, significantly antagonized paraoxon-induced lethality in mice. 1,3-Dioxane derivative 11 was an extremely potent antagonist of paraoxon-induced toxicity in mice, compared with prototypical protective agents physostigmine and pyridostigmine. Compound 11 exhibited a much more favorable therapeutic ratio than the reference drugs. The mechanism of action of 11 has not been elucidated, although it is concluded that it differs from that of hemicholinium-3 (inhibition of high-affinity, sodium-dependent uptake of choline into nerve terminals).
Cannon
J G
JG
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, Iowa City 52242.
Sahin
M F
MF
Long
J P
JP
Flynn
J R
JR
Bhatnagar
R K
RK
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis; D004146:Dioxanes / Q000138:chemical synthesis / Q000494:pharmacology*; D004147:Dioxins / Q000494:pharmacology*; D006426:Hemicholinium 3; D066298:In Vitro Techniques; D009469:Neuromuscular Junction / Q000187:drug effects*; D010078:Oxazines / Q000138:chemical synthesis / Q000494:pharmacology*; D010261:Paraoxon / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology*; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000494:pharmacology*; D011817:Rabbits; D009435:Synaptic Transmission / Q000187:drug effects
D002800:Cholinesterase Inhibitors; D004146:Dioxanes; D004147:Dioxins; D010078:Oxazines; D010880:Piperidines; D011759:Pyrrolidines; D006426:Hemicholinium 3; D010261:Paraoxon