Abstract

Alzheimer’s Disease (AD), Parkinson’s Disease (PD) and Lewy Body
Disease (LBD) are some of the many neurodegenerative disorders
associated with dementia, for which there is no ultimate cure. It is widely
accepted that central nervous system (CNS) nicotinic acetylcholine
receptors (nAChRs) may be strongly implicated in the pathology of these
devastating disorders, and that stimulation of nAChRs can enhance
cognitive behaviour in animals and humans. Nicotine and other nicotinic
receptor binding compounds have, over many years, been explored as
potential therapies for disorders such as AD and PD. This thesis describes
the preparation and pharmacological investigation of a series of 3-
substituted and 3,5-disubstitued pyridine derivatives as potential novel and
selective nictotinic receptor agonists.
Chapter Two details the synthesis of targeted compounds using the
generation of [(pyridin-3-yl)methyl]lithium and [(5-methylpyridin-3-
yl)methyl]lithium, respectively and subsequent reaction with various
electrophiles. Unsuccessful attempts at the synthesis of enantiomerically
pure 4-substituted arylpyridin-3-yl-ethanol derivatives by reduction of prochiral
4-substituted arylpyridin-3-yl-ethanone derivatives were made using
both catalytic and enzymatic approaches; however, a pair of
enantiomerically pure alcohols were isolated via the resolution of
diastereomeric esters (prepared by reaction with (S)-O-acetyl mandelic
acid) and subsequent hydrolysis.
iv
Chapter Three explores the synthesis of targeted compounds using
halogen-lithium exchange reactions of 3-bromopyridine using n-BuLi and
ring-opening by the resultant pyridin-3-yllithium of 4-substituted aryl
epoxides. As an extension, Sonogashira cross-coupling of 3-
bromopyridine and 4-substituted arylacetylenes and subsequent hydration
as an approach to 4-substituted pyridin-3-yl-ethanone derivatives is
described. A series of indole derivatives were synthesised using identical
approaches.
Using methodology developed in previous Chapters, Chapter Four
describes approaches to symmetrical and asymmetrical 3,5-
bis(arylethynyl)pyridine derivatives, the corresponding bis(ketones),
alcohols and 3,5-disubstituted keto-alcohol products.
Chapter Five details preliminary pharmacological data (binding and
functional assays) performed by our collaborators at Institut de
Recherches Servier.