The Design, Synthesis and Screening of Potential Pyridinium Oxime Prodrugs
Annual rept. 1 Mar 1983-29 Feb 1984
KANSAS UNIV LAWRENCE CENTER FOR BIOMEDICAL RESEARCH
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In an attempt to improve the delivery of quaternary pyridinium oxime regenerators of acetylcholinesterase AChE to the Central Nervous System CNS, structural analogs and prodrugs of N-methylpyridinium 2-carbaldoxime 2-PAM have been synthesized. The Series I prodrugs are dihydropyridinium oximes pro- 2-PAMs which possess electron withdrawing substituents in the 3- or 5- position. As precursors to these Series I prodrugs several 5-substituted-2-PAMs I, Br substituted and a 3-substituted 2-PAM I-substituted have been synthesized and characterized. In vitro and in vivo mice screening of these compounds indicates some promise as AChE regenerators, prompting the preparation of gram quantities of the I-substituted oximes for further biological evaluation. Efforts toward the synthesis of other 3- or 5-substituted CN, COHN2 substituted oximes were initiated. The Series II prodrugs are tetrahydropyridinium oximes were initiated. The Series II prodrugs are tetrahydropyridinium oximes which possess a labile ring substituent. These mashed prodrugs double latentiation are addition products of pro-2-PAM.