A topographical model of μ‐opioid and brain somatostatin receptor selective ligands NMR and molecular dynamics studies

WIESLAW M. KAZMIFRSKI, R. D. FERGUSON, ANDRZEJ W. LIPKOWSKI, VICTOR J. HRUBY

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

We have refined the 1H NMR‐based conformations of the μ‐opioid receptor selective peptides related to somatostatin of general formula Xxx‐Yyy1‐Cys‐Zzz‐D‐Trp‐Lys(Orn)5‐Thr‐Peh‐Thr8‐NH2, where Xxx, Yyy, Zzz are 0, d‐Phe and Tyr for 1; 0, d‐Tic and Tyr for 2; Gly, d‐Tic and Tyr for 3; and 0, d‐Phe and Tic for 4, respectively, (Kazmierski et al., J. Am. Chem. 113, 2275–2283), using a molecular‐dynamics approach. We present evidence that the NMR data are compatible with βII′‐, γ‐ and γ′‐turns for the central tetrapeptide Tyr‐D‐Trp‐Lys/Orn‐Thr. Based on detailed structural and topographical considerations, we suggest that the μ‐opioid receptor selectivity of 2 is due to a particular spatial arrangement of aromatic side chains of d‐Tic1 and Tyr3 (7.5 Å), and that the opioid receptor recognition domain is located in the N‐terminal part of the peptide while the somatostatin receptor recognition domain is determined by the central, turn forming part of this class of cyclic peptides. A model for a μ‐opioid selective ligand has emerged from these studies that shows excellent structural similarities to rigid opioid alkaloids.

Original languageEnglish (US)
Pages (from-to)265-278
Number of pages14
JournalInternational journal of peptide and protein research
Volume46
Issue number3-4
DOIs
StatePublished - Sep 1995

Keywords

  • model
  • molecular dynamics
  • nuclear magnetic resonance spectroscopy
  • topographical model
  • μ‐opioid antagonist
  • μ‐opioid ligand from somatostatin

ASJC Scopus subject areas

  • Biochemistry

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