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...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1990-02, Vol.33 (2), p.577-579
Main Authors: Cannon, Joseph G, Sahin, M. Fethi, Long, John Paul, Flynn, Jan R, Bhatnagar, Ranbir K
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Chemical and industrial products toxicology. Toxic occupational diseases
Chemical Phenomena
Chemistry
Cholinesterase Inhibitors - chemical synthesis
Dioxanes - chemical synthesis
Dioxanes - pharmacology
Dioxins - pharmacology
Hemicholinium 3
In Vitro Techniques
Medical sciences
Neuromuscular Junction - drug effects
Oxazines - chemical synthesis
Oxazines - pharmacology
Paraoxon - antagonists & inhibitors
Piperidines - chemical synthesis
Piperidines - pharmacology
Pyrrolidines - chemical synthesis
Pyrrolidines - pharmacology
Rabbits
Synaptic Transmission - drug effects
Toxicology
Various organic compounds
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Summary: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).
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00164a017