The Design, Synthesis and Screening of Potential Pyridinium Oxime Prodrugs.
Annual rept. 1 Mar 84-31 Jul 85,
KANSAS UNIV LAWRENCE CENTER FOR BIOMEDICAL RESEARCH
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In an attempt to improve the delivery a quaternary pyridinium oxime regenerators of acetycholinesterase AChE to the central nervous system CNS, structural analogs I and potential prodrugs II of N-methyl-pyridinium 2-carbaldoxime 2-PAM have been synthesized. The potential prodrugs are dihydropyridinium oximes pro-2-PAMs, which posses electron withdrawing substituents in the 3- or 5-position. As precursors to these prodrugs, we have synthesized and characterized this year a series of 5-substituted-2-PAMs C1, CH3, CN, COHN2 substituted and a series of 3-substituted-2-PAMs Br, C1, CH3 substituted. These new analogs and the 5-substituted 2-PAMs I, Br substituted and 3-substituted-2-PAM I substituted synthesized last year were tested in vitro for their ability to reactivate diisopropylfluorophosphate DEP-inactivated AChE, in vivo for their ability to protect mice from a challenge dose 2 X LD50 of DFP and, and in vivo for their ability to protect mice from a challenge dose 2x LD50 of Soman.