| Abstract
| - We describe the design, the conformational behavior, and the biological activity at the μ-opioidreceptor of new morphiceptin analogues. In these analogues a recently described dipeptidemimetic structure replaces both the N- and the C-terminal Xaa-Pro dipeptide of morphiceptin.Conformational investigation on the most active analogue, compared to the parent peptide,indicates a high degree of structural tolerance within the μ-opioid receptor binding site. Infact, our results indicate that only the location and the relative orientation of the side chainsof the aromatic pharmacophoric residues represent the indispensable structural features forμ-receptor binding. To reach such topological arrangement, opioid peptides can adopt differentconformations and configurations. In particular, opioid peptides bearing a proline residue asspacer between the two aromatic residues can adopt, in the active state, both cis and transconfigurations at the Tyr-Pro amide bond, each of them with the appropriate backbone andside chains orientations.
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