Novel oximes as blood-brain barrier penetrating cholinesterase reactivators.
The US Army utilizes pralidoxime (2-PAM) for the reactivation of OP-inhibited AChE. While 2-PAM effectively reactivates acetylcholinesterase (AChE) in the body, it does not cross the blood-brain barrier (BBB) at therapeutically relevant levels. To address this problem of central nervous system AChE reactivation, novel sugar-oxime conjugates were utilized. These 'sugar-oximes' would potentially be transported across the BBB because they contain a sugar moiety which would be recognized by the facilitative glucose transporters. Eight previously reported, but understudied sugar-oximes, as well as six novel sugar-oximes were synthesized, and their ability to reactivate both human red blood cell AChE and plasma butyrylcholinesterase poisoned with DFP, paraoxon, sarin and VX were tested. The results show that the novel sugar-oxime 13c was more active than the other compounds with a reactivation potential similar to 2-PAM. The sugar-oxime 8b had low toxicity with a LD(50) of 1,590 mg/kg from a single IM dose in the guinea pig and >2,000 mg/kg IP in the mouse. Histopathological analysis showed that there were no apparent differences in hippocampus, heart, liver, kidney sciatic nerve, or skeletal muscle between treated and untreated animals. These results show that sugar-oximes can be effective reactivators and suggest that high treatment doses may be possible.
Garcia
Gregory E
GE
Division of Biochemistry, Walter Reed Army Institute of Research, 503 Forney Ave, Silver Spring, MD 20910-7500, USA. gregory.e.garcia@us.army.mil
Campbell
Amy J
AJ
Olson
John
J
Moorad-Doctor
Deborah
D
Morthole
Venee I
VI
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002241:Carbohydrates / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D002801:Cholinesterase Reactivators / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology* / Q000633:toxicity; D004789:Enzyme Activation / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D051379:Mice; D010755:Organophosphates / Q000633:toxicity; D010091:Oximes / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology* / Q000633:toxicity; D018675:Toxicity Tests
D002241:Carbohydrates; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010755:Organophosphates; D010091:Oximes; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase