| Popis: |
The 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. |
