A topochemical model has been derived to account for the diverse selectivity of cyclic opioid peptides related to enkephalins and for narcotic alkaloids towards the $ mu$ and $ delta$ opiate subclasses. Efforts toward demonstrating its validity have later been accomplished. The model is based on a computer molecular modeling study using the opiate pharmacophore as a minimum prerequisite to align the molecules and benefit also of informations obtained from spectroscopic study in solution concerning the macrocycles conformation. The conformational properties of N$ sp alpha$Cbz-c((D)A$ sb2$Bu-Gly-Phe-Leu) were studied by nuclear Overhauser effect which provided semi-quantitative internuclear distances. One of the important elements that the model brings out is that the eventual presence of an aromatic ring on the beta carbon of Cys of the opioid peptide HTyr-(D)Pen-Gly-Phe-Cys-NH$ sb2$ should induce an increase in selectivity toward the 6 opiate subclass. Consequently, we engaged in preparing the special amino acid, P-phenylcysteine, using a method based on the addition of mercaptan to unsaturated azlactone. The diastereoisomers obtained were separated, and their relative configurations assigned by X-ray crystallography. The pure enantiomers were obtained by resolution with the enzyme carboxypeptidase A. Several difficulties were encountered during this preparation, the main concern being the S protecting group. This protecting group should be chosen with the property that it can be quantitatively removed when desired and compatible with the conditions of peptides synthesis. Moreover, the size of the protecting group should be minimized in order to be able to realize the resolution with the enzyme. We explored, by the same token, the size of the hydrophobic pocket of the exopeptidase. Using the structural information obtained from the X-Ray diffraction study of several of the $ beta$-phenycysteine, we have determined with the help of computer molecular modeling, the
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.28547 |
| Date | January 1994 |
| Creators | Villeneuve, Gérald Blaise |
| Contributors | Chan, Tak Hang (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Chemistry.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001424757, proquestno: NN00143, Theses scanned by UMI/ProQuest. |
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