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Potent side‐chain to side‐chain cyclized dermorphin analogues containing a carbonyl bridge
Author(s) -
Filip Katarzyna,
Oleszczuk Marta,
Pawlak Danuta,
Wójcik Jacek,
Chung Nga N.,
Schiller Peter W.,
Izdebski Jan
Publication year - 2003
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.510
Subject(s) - dermorphin , chemistry , side chain , peptide , stereochemistry , enkephalin , peptide synthesis , agonist , opioid peptide , cyclic peptide , oligopeptide , opioid , biochemistry , receptor , organic chemistry , polymer
A new family of cyclic opioid peptide analogues related to the 1–4 sequence of dermorphin/deltorphin (Tyr‐ D ‐Aaa 2 ‐Phe‐Aaa 4 ‐NH 2 ) has been synthesized. The synthesis of the linear precursor peptides was accomplished by the solid‐phase method and ring formation was achieved via a ureido group incorporating the side chain amino functions of D ‐Aaa 2 ( D ‐Lys, D ‐Orn) and Aaa 4 (Lys, Orn, Dab, Dap). The peptides were tested in the guinea‐pig ileum (GPI) and mouse vas deferens (MVD) assays. Most showed very high agonist potency in the GPI assay. The peptide containing D ‐Lys in position 2 and Dab in position 4 was 210 times more active than enkephalin, and that containing Orn and Dab, respectively, was 150 times more active than enkephalin. The latter peptide was also very active in the MVD assay, and showed an IC 50 MVD/GPI ratio of 0.816. NMR spectra of selected peptides were recorded, and structural parameters were determined. The conformational space of the peptides was examined using the electrostatically driven Monte Carlo method. With the help of the NMR spectra each peptide was described as an ensemble of conformations. The conformations have been interpreted with regard to the opioid activities, and comparisons have been made with a model proposed earlier for enkephalin analogues. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd.