Starting from the structure of Endomorphin-1 (Tyr-Pro-Trp-PheNH2), the endogenous ligand of mu-opioid receptor, we prepared modified peptides and peptidomimetics by introduction of unnatural amino acids, halogenation of the Trp, introduction of Pro-analogues, lipidization, and size reduction. The syntheses of (S)- or (R)-halo-tryphtophans and other Trp-analogues have been performed by tandem 1,4-addition and stereoselective enolate protonation of DHA-containing peptides. Otherwise, substituted tryphtophans have been prepared in optically pure form by enzymatic resolution. Oxazolidin-2-one 4-carboxylate has been introduced in position 2 of endomorphin-1 as a proline mimetic, to give a trans conformation of the Tyr1-Xaa2 peptide bond. Lipidization and a rationale search for focused structure modifications lead to the endomorphin mimetic N-Ac-D-Trp-Phe-Gly-NH2 and halo-substituted derivatives

DESIGN AND SYNTHESIS OF OPIOID PEPTIDE ANALOGUES AND MIMETICS

DE MARCO, ROSSELLA;GENTILUCCI, LUCA;TOLOMELLI, ALESSANDRA;SPAMPINATO, SANTI MARIO;BEDINI, ANDREA;
2011

Abstract

Starting from the structure of Endomorphin-1 (Tyr-Pro-Trp-PheNH2), the endogenous ligand of mu-opioid receptor, we prepared modified peptides and peptidomimetics by introduction of unnatural amino acids, halogenation of the Trp, introduction of Pro-analogues, lipidization, and size reduction. The syntheses of (S)- or (R)-halo-tryphtophans and other Trp-analogues have been performed by tandem 1,4-addition and stereoselective enolate protonation of DHA-containing peptides. Otherwise, substituted tryphtophans have been prepared in optically pure form by enzymatic resolution. Oxazolidin-2-one 4-carboxylate has been introduced in position 2 of endomorphin-1 as a proline mimetic, to give a trans conformation of the Tyr1-Xaa2 peptide bond. Lipidization and a rationale search for focused structure modifications lead to the endomorphin mimetic N-Ac-D-Trp-Phe-Gly-NH2 and halo-substituted derivatives
2011
R.De Marco; L. Gentilucci; A. Tolomelli; S. Feddersen; S. Spampinato; A. Bedini; R. Artali.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/105366
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