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 / R.De Marco; L. Gentilucci; A. Tolomelli; S. Feddersen; S. Spampinato; A. Bedini; R. Artali.. - In: PHARMACOLOGICAL REPORTS. - ISSN 1734-1140. - STAMPA. - 63:(2011), pp. 226-226.
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 derivativesI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.