Design and synthesis of receptor-selective peptide ligands, and the synthesis of unnatural amino acids.
AuthorLung, Feng-Di Tiffany.
Committee ChairHruby, Victor J.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractThe discovery of endogenous opioid peptides has greatly accelerated research in opioid chemistry and biology. Studies of the physiological and pharmalogical roles of these receptors require highly potent and receptor-selective ligands for μ, δ, and κ receptors. The major goal of this project is to design and synthesize highly potent and κ receptor-selective dynorphin A analogues with specific conformational and topographical features. Therefore, a series of linear and cyclic dynorphin A analogues with global and/or local conformational constraints have been designed, synthesized, and evaluated for their biological activities. Several leads from dynorphin A analogues have been developed, and have provided new insights into requirements for high κ receptor-selectivity and potency. The incorporation of side chain conformationally constrained amino acids can provide new insights into topographical requirements for peptide ligand-receptor binding. An efficient synthesis of 2', β-dimethyltyrosine in large quantities and a new strategy of the synthesis of optically pure isomers of β-methylphenylalanine derivatives have been developed. These unnatural amino acids can be incorporated into peptides for the development of novel peptides with high potency and enhanced receptor-selectivity.