Glycosylation improves the central effects of DAMGO

John J. Lowery, Larisa Yeomans, Charles M. Keyari, Peg Davis, Frank Porreca, Brian I. Knapp, Jean M. Bidlack, Edward J. Bilsky, Robin Polt

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

A series of μ-agonist DAMGO analogs were synthesized and pharmacologically characterized to test the 'biousian' hypothesis of membrane hopping. DAMGO was altered by incorporating moieties of increasing water solubility into the C-terminus via carboxamide and simple glycoside additions. The hydrophilic C-terminal moieties were varied from glycinol in DAMGO (1) to l-serine amide (2), l-serine amide β-d-xyloside (3), l-serine amide β-d-glucoside (4), and finally to l-serine amide β-lactoside (5). Opioid binding and mouse tail-flick studies were performed. Antinociceptive potency (intravenous) increased, passing through a maximum (A50 ≈ 0.2 μmol/kg) for 2 and 3 as membrane affinity versus water solubility became optimal, and dropped off (A50 ≈ 1.0 μmol/kg) for 4 and 5 as water solubility dominated molecular behavior. Intravenous A50 values were plotted versus hydrodynamic values (glucose units, g.u.) for the glycoside moieties, or the hydrophilic/hydrophobic Connolly surface areas (A50 versus e-Awater/Alipid), and provided either a V-shaped or a U-shaped curve, as predicted by the 'biousian' hypothesis. The μ-selective receptor profile was maintained (Ki's = 0.66-1.3 nm) upon modifications at the C-terminus. The optimal 'degree of glycosylation' for the DAMGO peptide message appears to be between 1.25 and 1.75 g.u. (hydrodynamic g.u.), or 0.75 and 0.90 in terms of the surface-derived amphipathicity values.

Original languageEnglish (US)
Pages (from-to)41-47
Number of pages7
JournalChemical Biology and Drug Design
Volume69
Issue number1
DOIs
StatePublished - Jan 1 2007

Keywords

  • Amphipathicity
  • Antinociception
  • Biousian
  • Blood-brain barrier
  • DAMGO
  • Drug delivery
  • Enkephalin
  • Glycopeptide

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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  • Cite this

    Lowery, J. J., Yeomans, L., Keyari, C. M., Davis, P., Porreca, F., Knapp, B. I., Bidlack, J. M., Bilsky, E. J., & Polt, R. (2007). Glycosylation improves the central effects of DAMGO. Chemical Biology and Drug Design, 69(1), 41-47. https://doi.org/10.1111/j.1747-0285.2007.00462.x