Accession Number : ADA189325

Title :   The Design, Synthesis and Screening of Potential Pyridinium Oxime Prodrugs.

Descriptive Note : Annual rept. 1 Mar 82-28 Feb 83,

Corporate Author : KANSAS UNIV LAWRENCE CENTER FOR BIOMEDICAL RESEARCH

Personal Author(s) : Borchardt, Ronald T ; Simmons, John E

PDF Url : ADA189325

Report Date : 01 Mar 1983

Pagination or Media Count : 56

Abstract : In an attempt to improve the CNS delivery of quaternary pyridinium oxime regenerators of acetylcholinesterase (AChE), we have initiated chemical and biochemical studies on structural analogs and prodrug forms of N-methylpyridinium 2-carbaldoxime (2-PAM, 7). Over the past year we have concentrated our efforts on synthesizing two basic types of Pro-PAM derivatives. Series I are dihydropyridinium oximes 1 and 2 which possess electron withdrawing substituents in the 3- or 5-position. These compounds require oxidation (latentation) to generate the substituted 2-PAMs 5 and 6. It is hoped that the electron withdrawing substituent will stabilize the dihydropyridine structure and produce a slow in vitro conversion. Series II are tetra-hydropyridinium oximes 3 which possess a labile ring substituent. These masked prodrugs (double latentation) are addition products of dihydropyridinium oxime 4 (Pro-2-PAM) and require a two step (elimination and oxidation) conversion to the active quaternary oxime 7 (2-PAM).

Descriptors :   *ACETYLCHOLINESTERASE, *BIOCHEMISTRY, *PYRIDINES, *OXIMES, ANALOGS, CENTRAL NERVOUS SYSTEM, CONVERSION, DELIVERY, ELECTRONS, IN VITRO ANALYSIS, OXIDATION, STRUCTURAL PROPERTIES, SYNTHESIS(CHEMISTRY)

Subject Categories : Organic Chemistry

Distribution Statement : APPROVED FOR PUBLIC RELEASE