Alanine containing analogues of cyclo(-d-pro-phe-thr-lys(z)-trp-phe-)- conformationally controlled structure-activity-relationships

✍ Scribed by H. Kessler; G. Gemmecker; A. Haupt; M. Klein; K. Wagner; M. Will

• Book ID: 104203725
• Publisher: Elsevier Science
• Year: 1988
• Tongue: French
• Weight: 903 KB
• Volume: 44
• Category: Article
• ISSN: 0040-4020
• DOI: 10.1016/s0040-4020(01)86114-7

✦ Synopsis

Six analogues of the cyclic hexapeptide cyclo(-D-Pro-Phe-Thr-Lys(Z)-Trp-Phe-) (1) were synthesized in which each amino acid was substituted by an alanine or Dalanine residue, respectively. Their conformation was determined by two-dimensional NMR-spectroscopy and refined by restraint molecular dynamics calculations (MD). The backbone conformation of five of these derivatives is identical to the parent peptide 1. Only the peptide in which the Thr residue is substituted by an Ala residue shows a change of the backbone in the Ala-Lys-Trp-Phe region, which is obviously induced by the lack of the Thr hydroxyl group. This hydroxyl group takes part in strong intramolecular hydrogen bonds in I. However, the population of the side chain rotamers is almost identical in all analogues. Thus, the comparison of the activities in the inhibition of the cholate uptake of isolated hepatocytes with the conformations of these peptides leads to the result that the aromatic side chains are important to achieve high activity.