Nonquaternary reactivators for organophosphate-inhibited cholinesterases.
A new class of amidine-oxime reactivators of organophosphate (OP)-inhibited cholinesterases (ChE) was synthesized and tested in vitro and in vivo. Compared with 2-PAM, the most promising cyclic amidine-oxime (i.e., 12e) showed comparable or greater reactivation of OP-inactivated AChE and OP-inactivated BChE. To the best of our knowledge, this is the first report of a nonquaternary oxime that has, comparable to 2-PAM, in vitro potency for reactivation of Sarin (GB)-inhibited AChE and BChE. Amidine-oximes were tested in vitro, and reactivation rates for OP-inactivated butyrylcholinesterase (BChE) were greater than those for 2-PAM or MINA. Amidine-oxime reactivation rates for OP-inactivated acetylcholinesterase (AChE) were lower compared to 2-PAM but greater compared with MINA. Amidine-oximes were tested in vivo for protection against the toxicity of nerve agent model compounds. (i.e., a model of Sarin). Post-treatment (i.e., 5 min after OP exposure, i.p,) with amidine oximes 7a-c and 12a, 12c, 12e, 12f, and 15b (145 μmol/kg, i.p.) protected 100% of the mice challenged with the sarin model compound. Even at 25% of the initial dose of amidine-oxime (i.e., a dose of 36 μmol/kg, i.p.), 7b and 12e protected 100% of the animals challenged with the sarin nerve agent model compound that caused lethality in 6/11 animals without amidine-oxime.
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, California 92121, United States.
Jarosław
J
Kalisiak
Erik C
EC
Ralph
John R
JR
Cashman
D000110:Acetylcholinesterase / Q000378:metabolism; D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000506:poisoning*; D002800:Cholinesterase Inhibitors / Q000506:poisoning*; D002802:Cholinesterases / Q000378:metabolism*; D004793:Enzyme Reactivators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D051379:Mice; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011041:Poisoning / Q000401:mortality / Q000517:prevention & control; D012524:Sarin / Q000506:poisoning*; D013329:Structure-Activity Relationship
D000578:Amidines; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D004793:Enzyme Reactivators; D010091:Oximes; D012524:Sarin; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002802:Cholinesterases