Synthesis, biology, NMR and conformation studies of the topographically constrained δ-opioid selective peptide analogs of [β-iPrPhe3]deltorphin I

S. Liao, M. Shenderovich, Z. Zhang, V. J. Hruby, K. E. Kövér, K. Hosohata, P. Davis, F. Porreca, H. I. Yamamura

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Replacement of Phe3 in the endogenous δ-opioid selective peptide deltorphin I with four optically pure stereoisomers of the topographically constrained, highly hydrophobic novel amino acid β-isopropylphenylalanine (β-iPrPhe) produced four pharmacologically different deltorphin I peptidomimetics. Radiolabeled ligand-binding assays and in vitro biological evaluation indicate that the stereoconfiguration of the iPrPhe residue plays a crucial role in determining the binding affinity, bioactivity and selectivity of [β-iPrPhe3]deltorphin I analogs: a (2S,3R) configuration of the iPrPhe3 residue in [β-iPrPhe3]deltorphin I provided the most desirable biological properties with binding affinity (IC50=2 nM), bioassay potency (IC50=1.23 nM in MVD assay) and exceptional selectivity for the δ-opioid receptor over the μ-opioid receptor (30 000). Further conformational studies based on two-dimensional NMR and computer-assisted molecular modeling suggested a model for the possible bioactive conformation in which the Tyr1 and (2S, 3R)-β-iPrPhe3 residues adopt trans side-chain conformations, and the linear peptide backbone favors a distorted β-turn conformation.

Original languageEnglish (US)
Pages (from-to)257-276
Number of pages20
JournalJournal of Peptide Research
Volume57
Issue number4
DOIs
StatePublished - 2001
Externally publishedYes

Keywords

  • Bioactive conformation
  • Deltorphin
  • NMR
  • Opioid peptides
  • β-isopropylphenylalanine

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

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