We describe the design, the conformational behavior, and the biological activity at they-opioid receptor of new morphiceptin analogues. In these analogues a recently described dipeptide mimetic 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. In fact, our results indicate that only the location and the relative orientation of the side chains of the aromatic pharmacophoric residues represent the indispensable structural features for μ-receptor binding. To reach such topological arrangement, opioid peptides can adopt different conformations and configurations. In particular, opioid peptides bearing a proline residue as spacer between the two aromatic residues can adopt, in the active state, both cis and trans configurations at the Tyr(1)-Pro(2) amide bond, each of them with the appropriate backbone and side chains orientations.

Morphiceptin analogues containing a dipeptide mimetic structure: An investigation on the bioactive topology at the mu-receptor

GIUSTI, LAURA;CALDERONE, VINCENZO;MAZZONI, MARIA ROSA;
2005-01-01

Abstract

We describe the design, the conformational behavior, and the biological activity at they-opioid receptor of new morphiceptin analogues. In these analogues a recently described dipeptide mimetic 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. In fact, our results indicate that only the location and the relative orientation of the side chains of the aromatic pharmacophoric residues represent the indispensable structural features for μ-receptor binding. To reach such topological arrangement, opioid peptides can adopt different conformations and configurations. In particular, opioid peptides bearing a proline residue as spacer between the two aromatic residues can adopt, in the active state, both cis and trans configurations at the Tyr(1)-Pro(2) amide bond, each of them with the appropriate backbone and side chains orientations.
2005
Grieco, P; Giusti, Laura; Carotenuto, A; Campiglia, P; Calderone, Vincenzo; Lama, T; Gomez Monterrey, I; Tartaro, G; Mazzoni, MARIA ROSA; Novellino, E.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/184427
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