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Proton NMR Conformational Analysis of Cyclic β‐Casomorphin Analogues of the Type Tyr‐cyclo[‐N ω ‐D‐Orn‐Xaa‐Yaa‐Gly‐]
Author(s) -
MrestaniKlaus Carmen,
Brandt Wolfgang,
Schmidt Ralf,
Neubert Klaus,
Schiller Peter W.
Publication year - 1996
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.19963290305
Subject(s) - chemistry , conformational isomerism , stereochemistry , hydrogen bond , intramolecular force , amide , moiety , peptide bond , agonist , nuclear magnetic resonance spectroscopy , peptide , cyclic peptide , proton nmr , chemical shift , crystallography , molecule , receptor , organic chemistry , biochemistry
A conformational study of the cyclic β‐casomorphin‐5 analogues H‐Tyr‐cyclo[‐D‐Orn‐2‐Nal‐Pro‐Gly‐] ( 1 ) (μ‐selective agonist; 2‐Nal = 2‐naphthylalanine), H‐Tyr‐cyclo[‐D‐Orn‐2‐Nal‐D‐Pro‐Gly‐] ( 2 ) (mixed μ agonist/δ antagonist) and H‐Tyr‐cyclo[‐D‐Orn‐Phe‐D‐Pro‐Gly‐] ( 3 ) (highly potent μ and δ agonist) has been carried out using 1 H NMR spectroscopy. A complete assignment of the proton resonances of the three pentapeptides has been achieved. Compound 1 was shown to exist in two conformations, a major one (90%) characterized by a cis amide bond between 2‐Nal 3 and Pro 4 , and a minor one (10%) showing cis amide bonds both between D‐Orn 2 and 2‐Nal 3 and between 2‐Nal 3 and Pro 4 . Peptides 2 and 3 each showed only one conformer with all‐trans peptide bonds in both cases. Temperature dependence studies of the amide proton chemical shifts indicated the existence of several intramolecular hydrogen bonds in the case of compounds 2 and 3 but not in the case of peptide 1. The backbone conformations of 2 and 3 were found to be similar, both being characterized by two consecutive γ turns around the D‐Pro 4 and D‐Orn 2 residues, respectively, and by a D‐Orn 2 ‐CO←HN δ ‐D‐Orn 2 hydrogen bond. Altogether, the overall backbone conformation and the preferred side chain conformation were found to be roughly similar for the three title peptides. For all three compounds a close proximity between the aromatic moiety of the 3‐position residue (2‐Nal or Phe) and the D(or L)‐Pro 4 residue was established on the basis of ROESY experiments. The examination of low energy conformations obtained in molecular modelling studies by taking into account the various experimentally found NMR parameters (NOEs, vicinal H,H coupling constants, torsion angles, H‐bonds) led to proposals of the solution conformation for each peptide. These conformations are in close agreement with a pharmacophore model for μ opioid receptor binding compounds.