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Title: Synthesis of analogues of epibatidine
Author: Cox, Caroline D.
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2000
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Our intentions were to design epibatidine analogues containing a distance between the two active nitrogen centres close to that shown by epibatidine itself, in concordance with the current pharmacophore. A range of four different 5- and 6-chloropyridyl-substituted-2-azabicyclo[2.2.1]-heptane derivatives was constructed. The azabicyclic skeleton was made via a Diels-Alder reaction between cyclopentadiene and an iminium ion. The 5- and 6-exo-chloropyridyl derivatives were synthesised using a reductive Heck reaction to couple the chloropyridyl ring onto the exo- face of the azabicycle, 5- and 6-endo- chloropyridine onto the appropriate azabicyclic ketone. Dehydration of the adduct followed by reduction from the exo-face of the azabicycle ensured that the chloropyridine ring was in the endo- orientation. 1H NMR spectroscopy was used to characterise these compounds. Preliminary pharmacological testing of the four molecules on rat tissue revealed that both endo- analogues were as active as epibatidine at the nicotinic receptor and that both the exo- and endo- isomers showed improved selectivity for the 4 sub-type of this receptor as compared to the 7. As an extension of the design of analogues having a controlled N-N orientation and distance, two tropane-based spirocyclic epibatidine analogues have been synthesised. Both molecules were made from topionone by functionalisation of the 3-keto-carbon. Characterisation of both molecules was carried out using 1H NMR spectroscopy. The absolute configuration of one of the analogue molecules was confirmed by X-ray crystallography.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available