isonitrosoacetone and Organophosphate-Poisoning

A new class of amidine-oxime reactivators of organophosphate (OP)-inhibited cholinesterases (ChE) were designed, synthesized, and tested. These compounds represent a novel group of oximes with enhanced capabilities of crossing the blood-brain barrier. Lack of brain penetration is a major limitation for currently used oximes as antidotes of OP poisoning. The concept described herein relies on a combination of an amidine residue and oxime functionality whereby the amidine increases the binding affinity to the ChE and the oxime is responsible for reactivation. Amidine-oximes were tested in vitro and reactivation rates for OP-BuChE were greater than pralidoxime (2-PAM) or monoisonitrosoacetone (MINA). Amidine-oxime reactivation rates for OP-AChE were lower compared to 2-PAM but greater compared with MINA. After pretreatment for 30 min with oximes 15c and 15d (145 μmol/kg, ip) mice were challenged with a soman model compound. In addition, 15d was tested in a post-treatment experiment (145 μmol/kg, ip, administration 5 min after sarin model compound exposure). In both cases, amidine-oximes afforded 100% 24 h survival in an animal model of OP exposure.

Topics: Acetylcholinesterase; Amidines; Animals; Blood-Brain Barrier; Butyrylcholinesterase; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterases; Enzyme Reactivators; Female; Humans; Mice; Organophosphate Poisoning; Organophosphorus Compounds; Oximes; Permeability; Recombinant Proteins; Sarin; Soman; Structure-Activity Relationship

Topics: Acetylcholinesterase; Animals; Antidotes; Body Temperature; Cattle; Chemical Phenomena; Chemistry; Dose-Response Relationship, Drug; Enzyme Reactivators; Female; Goats; Guinea Pigs; Half-Life; In Vitro Techniques; Lethal Dose 50; Male; Mice; Organophosphate Poisoning; Organophosphorus Compounds; Oximes; Rabbits; Rats; Rats, Inbred Strains; Sarin; Solubility; Structure-Activity Relationship