Ring Substituted and Other Conformationally Constrained Tyrosine Analogues of [d-Pen2,d-Pen5]enkephalin with δ Opioid Receptor Selectivity

K. C. Russell, Geoffrey Landis, Thomas H. Kramer, Lei Fang, Richard Knapp, Peg Davis, Thomas F. Burks, Henry I. Yamamura, Victor J. Hruby, Geza Toth

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

The conformationally restricted, cyclic disulfide-containing δ opioid receptor selective enkephalin analogue [d-Pen2, d-Pen6]enkephalin (DPDPE) was modified by 2′ (CH3) and 3′ (I, OCH3, NO2, NH2) ring substitutions and by β-methyl conformationally constrained β-methyltyrosine derivatives in the 1 position. The potency and selectivity of these analogues were evaluated by bioassay in the mouse vas deference (MVD, δ receptor assay) and guinea pig ileum (GPI, μ receptor assay) assays and by radioreceptor binding assays in the rat brain using [3H]CTOP (μ ligand) and [3H] [p-CIPhe4]DPDPE (δ ligand). The analogues showed highly variable potencies in the binding assays and in the bioassays. Aromatic ring substituents with positive Hammett constants had decreased potency, while substituents with negative Hammett constants has increased potency for the opioid receptor. The most potent and most selective compound based on the binding was [2′-MeTyr1]DPDPE (IC50 = 0.89 nM and selectivity ratio 1310 in the binding assays). The 6-hydroxy-2-aminotetralin-2-carboxylic acid-containing analogue, [Hat1]DPDPE, also was highly potent and selective in both assays, demonstrating that significant modifications of tyrosine in enkephalins are possible with maintenance of high potency and δ opioid receptor selectivity. Of the β-methyl-substituted Tyr1 analogues, [(2S,3R)-β-MeTyr1]DPDPE was the most potent and receptor selective. The results with substitution of β-MeTyr or Hat instead of Tyr also demonstrate that topographical modification in a conformationally restricted ligand can significantly modulate both potency and receptor selectivity of peptide ligands that have multiple sites of biological activity.

Original languageEnglish (US)
Pages (from-to)2384-2391
Number of pages8
JournalJournal of Medicinal Chemistry
Volume35
Issue number13
DOIs
StatePublished - Jun 1 1992

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Ring Substituted and Other Conformationally Constrained Tyrosine Analogues of [d-Pen<sup>2</sup>,d-Pen<sup>5</sup>]enkephalin with δ Opioid Receptor Selectivity'. Together they form a unique fingerprint.

  • Cite this

    Russell, K. C., Landis, G., Kramer, T. H., Fang, L., Knapp, R., Davis, P., Burks, T. F., Yamamura, H. I., Hruby, V. J., & Toth, G. (1992). Ring Substituted and Other Conformationally Constrained Tyrosine Analogues of [d-Pen2,d-Pen5]enkephalin with δ Opioid Receptor Selectivity. Journal of Medicinal Chemistry, 35(13), 2384-2391. https://doi.org/10.1021/jm00091a006