Synthesis and Assay of Novel Pyridinium Oximes with Potential Activity in the Central Nervous System for Reactivating Phosphorylated Acetylcholinesterase (sponsored by the Department of Defense/DTRA)
The objective of this grant is to synthesize and test, both in vitro and in vivo, novel oximes that can cross the blood-brain barrier and therefore will be capable of reactivating brain acetylcholinesterase (AChE) that has been inhibited by surrogates for the nerve agents sarin and soman. The synthesis will produce a series of phenoxyalkyl pyridinium oximes that are sufficiently lipophilic to cross the blood-brain barrier. These experiments will be performed at MSU within the Center for Environmental Health Sciences. This research at MSU will complement the on-going intramural research on physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling occurring at the AFRL/HEPB, Wright Patterson Air Force Base, Ohio. In summary, this project will synthesize novel lipophilic phenoxyalkyl pyridinium oximes, will compare these newly synthesized oximes to the currently approved oxime reactivator 2-PAM in in vitro and in vivo studies, and will perform PBPK/PD modeling to gain a better understanding of the disposition of the oxime and chemical warfare agents.