Development of novel nicotinic receptor mediated therapeutic agents: Synthesis and biological evaluation of novel epibatidine analogs and the first total synthesis of (+/-)-anabasamine and related analogs

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 α4β2 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-tropmone 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.