Hemicholinium-3 congeners as potential antagonists to organophosphate-induced toxicity

• Published in: Journal of medicinal chemistry Vol. 33; no. 2; pp. 577 - 579
• Main Authors: Cannon, Joseph G, Sahin, M. Fethi, Long, John Paul, Flynn, Jan R, Bhatnagar, Ranbir K
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-02-1990
• 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; Vertebrata; Cholinergic receptor; Mammalia; Structure activity relation; Mouse; Toxicity; Animal; Rodentia; Organophosphorus compounds; Antagonist; Antidote; Neuromuscular transmission
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00164a017

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).