Topographically Designed Analogues of [formula omitted] enkephalin

Victor J. Hruby, Catherine A. Gehrig, Lung Fa Kao, Geza Toth, Richard Knapp, George K. Lui, Henry I. Yamamura, Thomas H. Kramer, P. Davis, Thomas F. Burks

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

Abstract

The conformationally restricted, cyclic disulfide-containing δ opioid receptor selective enkephalin analogue [formula omitted] enkephalin (1, DPDPE) was systematically modified topographically by addition of a methyl group at either the pro-S or pro-R position of the β carbon of an L-Phe4 or D-Phe4 residue to give [(2S,3S)-β-MePhe4]DPDPE (2), [(2R,3R)-β-MePhe4]DPDPE (3), [(2S,3R)-β-MePhe4]DPDPE (4), and [(2R,3S)-β-MePhe4]DPDPE (5). The four corresponding isomers were prepared in which the β-methylphenylalanine residue was p-nitro substituted, that is with a β-methyl-p-nitrophenylalanine (β-Me-p-NO2Phe) residue, to give [(2S,3S)-β-Me-p-NO2Phe4]DPDPE (6), [(2R,3R)-β-Me-p-NO2Phe4]DPDPE (7), [(2S,3R)-β-Me-p-NO2Phe4]DPDPE (8), and [(2R,3S)-β-Me-p-NO2Phe4]DPDPE (9), respectively. The potency and selectivity (δ vs μ opioid receptor) were evaluated by radioreceptor binding assays in the rat brain using [3H]CTOP (μ ligand) and [3H]DPDPE (δ ligand) and by bioassay with mouse vas deferens (MVD, δ receptor assay) and guinea pig ileum (GPI, μ receptor assay). The eight analogues of DPDPE showed highly variable binding and bioassay activities particularly at the δ opioid receptor (4 orders of magnitude), but also at the μ opioid receptor, which led to large differences (3 orders of magnitude) in receptor selectivity. For example, [(2S,3S)-β-MePhe4]DPDPE (2) is 1800-fold selective in binding to the δ vs μ receptor, making it one of the most selective δ opioid receptor ligands in the enkephalin series as assessed by the rat brain binding assay, whereas the corresponding (2R,3R)-β-Me-p-NO2Phe-containing analogue 9 is only 4.5-fold selective (nonselective) in this same assay. On the other hand, in the bioassay systems, [(2S,3S)-β-Me-p-NO2Phe4]DPDPE (5) is more potent than DPDPE and 8800-fold selective for the MVD (δ receptor) vs the GPI (μ receptor), making it the most highly selective ligand in this series for the i opioid receptor on the basis of these bioassays. In these assay systems, the (2R,SS)-β- MePhe4-containing analogue 5 had very weak potency and virtually no receptor selectivity (4.4-fold). These results demonstrate that topographical modification alone in a conformationally restricted peptide ligand can significantly modulate both potency and receptor selectivity of peptide ligands that have multiple sites of biological activity and suggest that this approach may have general application to peptide ligand design.

Original languageEnglish (US)
Pages (from-to)1823-1830
Number of pages8
JournalJournal of Medicinal Chemistry
Volume34
Issue number6
DOIs
StatePublished - Jun 1 1991

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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