Date of Award

8-7-2003

Degree Type

Dissertation

Degree Name

Ph.D.

Degree Program

Chemistry

Department

Chemistry

Major Professor

Trudell, Mark

Second Advisor

Jursic, Branko

Third Advisor

Wang, Guijun

Fourth Advisor

Wiley, John

Fifth Advisor

Rick, Steven

Abstract

In an effort to search for a more selective, less toxic neuronal nicotinic acetylcholine receptor analgesic agent in comparison to epibatidine, a series of analogs with hybrid structures of epibatidine and ABT-594 were designed and synthesized. The 1-(pyridyloxymethyl)-7-azabicyclo[2.2.1]heptane ring systems were furnished via an intramolecular cyclization from a trans 1, 4 disubstitituted amino-cyclohexane derivative. The functionalized cyclohexane ring was formed via a [4+2] Diels-Alder cyclization reaction between the acetamidoacrylate and Danishefsky's diene. These 1- (pyridyloxymethyl)-7-azabicyclo[2.2.1]heptane ring systems were then tested in vitro as potential á4â2 nicotinic acetylcholine receptor ligands with high potency and selectivity. In addition, a series of rigid acetylcholine analogs were synthesized from cocaine to study the conformation of acetylcholine, the endogenous neurotransmitter at the nicotinic acetylcholine receptor. A stereoselective reduction of 2-tropinone led to the enantioselective synthesis of the desired acetoxytropane systems. These compounds were also tested in in vivo models for binding affinity and efficacy responses. Anabasamine, an alkaloid isolated from the Central Asian shrub, Anabasis aphylla, was synthesized for the first time. It was targeted due to interesting preliminary biological activity such as exhibiting anticholinesterase activity, anti-inflammatory activity, and facilitated an increase in hepatic alcohol dehydrogenase levels. Only preliminary studies were performed as anabasamine is limited in quantity due to its difficult isolation. A versatile synthetic methodology was developed for the synthesis of anabasamine and related nicotine analogs. This new methodology employed a pyridyl anion addition to valerolactone, for anabasamine, or butyrolactone for the nicotine analog, to afford 5-hydroxy-1-(6-methoxy-pyridin-3-yl)-pentan-1-one or 4-hydroxy-1-(6- methoxy-pyridin-3-yl)-butan-1-one, respectively. A reductive amination provided the piperidine ring moiety and a Suzuki coupling reaction introduced the bipyridyl moiety to anabasamine in five steps and 23% overall yield. In addition, this methodology was applied successfully to the synthesis of nicotine and other related analogs. In particular the synthesis of 6-methoxynicotine, a useful drug intermediate, was generated improving the yield from 16% over five steps to 54% over three steps.

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The University of New Orleans and its agents retain the non-exclusive license to archive and make accessible this dissertation or thesis in whole or in part in all forms of media, now or hereafter known. The author retains all other ownership rights to the copyright of the thesis or dissertation.

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