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Synthesis, structural and biological studies of potential 5-HT3 receptor antagonists

Whelan, Brendan A (1994) Synthesis, structural and biological studies of potential 5-HT3 receptor antagonists. PhD thesis, Dublin City University.

This thesis involves the syntheses of new compounds as potential antagonists of the 5- HT3 receptor, a sub-group of the serotonin receptors. The objective of the work can be considered two fold: The primary aim, which can be regarded as the principal goal, was the design and chemical synthesis of new molecules which could antagonise the 5 -HT3 receptor and thus lead to new drug substances which could be effective in the treatment of illnesses associated with this receptor, among which may be included the control of emesis in cancer patients receiving chemotherapy. Secondly, by carrying out the structural and conformational studies of the synthesised compounds and relating these to the biological studies it was hoped to elucidate more information on the nature of the 5 -HT3 receptor, the structure of which is unknown. Three series of potential antagonists were synthesised. The first series involves a tropane spiroimidazoline molecule with various aromatic substituents in the 2 ' position of the imidazoline ring (the final compounds of this series have been numbered I a-g throughout the text, the number I referring to the number of the series and the letters a-g to the individual final products within the series) The structure represents a novel feature within the known 5 -HT3 antagonists. A second series of products (II a-g) was synthesised in which the tropane function of the molecule was replaced by a bicyclic quinuclidine system. The synthetic method developed for the syntheses of these 2'-aryl- 8-methyl-8-azabicyclo[3.2. l]octane-3-spiro 4'(5')-imidazolines and 2'-aryl-l-azabicyclo[ 2.2.2]octane-3-spiro-4'(5')-imidazo-lines takes place via the reaction of an azabicyclic 1,2-diamines with aryl imidate salts. Competing reactions in the syntheses of the 1,2-diamines such as the reduction of aminonitriles with LiAlFLj lead to some anomalous products. In the Pinner synthesis of the imidates, unstable pyridine type imidates were stabilised as their A'-oxide derivatives. A third series of tropane 1,2,4-oxadiazoles (III a-g) was synthesised via the reaction of exo-3-carbomethoxy-8-methyl-8-azabicyclo[3.2.1]octane with aryl amidoximes. The former tropinone carbomethoxy ester was synthesised in a high yielding stereospecific synthesis from tropinone, via the intermediacy of 3-(l,3-dithiane-2-ylidene)-8-methyI- 8-azabicyclo[3.2. ljoctane. The structural and conformational analysis of the compounds shows that in solution the tropinone moiety in both the tropinone spiroimidazolines and the tropinone oxadiazoles adopts a chair-envelope conformation for the piperidine and pyrrolidine rings respectively, with the piperidine ring in a slightly flattened disposition. The N-methyl group adopts an equatorial position with respect to the six membered piperidine ring. Xray structural analysis for one compound in each of the tropinone series showed that a similar conformation was observed for the tropinone systems in the solid state. In the tropinone imidazoline series the aromatic indole group attached to the imidazoline ring was conjugated with the latter thus forming an almost planar structure, a phenomenon which was also observed,in solution, and thus provides an important feature for 5 -HT3 antagonists. Pharmacological and biochemical studies indicated that one compound in each of the spiroimidazoline series (those containing the dichlorophenyl aromatic substituent) displayed 5 -HT3 antagonistic properties comparable to MDL 72222 a potent 5 -HT3 receptor antagonist. These activity results, combined with the structural analysis, led to the conclusion that the imidazoline group was acting as an bioisosteric replacement for a carbonyl function and as such is the first time this system has been reported in 5 -HT3 antagonists. The oxadiazole series likewise displayed several biologically active molecules of which the most active was again that containing the dichlorophenyl substituent as the aromatic portion of the molecule.
Item Type:Thesis (PhD)
Date of Award:1994
Supervisor(s):James, Paraic and Galvez, Enrique
Uncontrolled Keywords:Organic compounds (Synthesis); Serotonin receptors; 5-HT3 receptor
Subjects:Physical Sciences > Chemistry
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health > School of Chemical Sciences
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 License. View License
ID Code:19466
Deposited On:03 Oct 2013 15:15 by Celine Campbell . Last Modified 03 Oct 2013 15:15

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