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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:576530 |
| Date | January 2009 |
| Creators | Colgin, Neil |
| Publisher | University of Sunderland |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://sure.sunderland.ac.uk/4064/ |
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