Phosphorylation of enkephalins: NMR and CD studies in aqueous and membrane-mimicking environments

Larisa Yeomans, Dhanasekaran Muthu, John J. Lowery, Heather N. Martinez, Leif Abrell, Guanxin Lin, Kyle Strom, Brian I. Knapp, Jean M. Bidlack, Edward J. Bilsky, Robin Polt

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Phosphorylation of l-serine-containing enkephalin analogs has been explored as an alternative to glycosylation in an effort to increase blood-brain barrier permeability and CNS bioavailability of peptide pharmacophores. Two enkephalin-based peptides were modified for these studies, a set related to DTLES, a mixed μ/δ-agonist, and one related to DAMGO, a highly selective μ-agonist. Each unglycosylated peptide was compared to its phosphate, its mono-benzylphosphate ester, and its β-d-glucoside. Binding was characterized in membrane preparations from Chinese hamster ovary cells expressing human μ, δ and κ-opiate receptors. Antinociception was measured in mice using the 55°C tail-flick assay. To estimate bioavailability, the antinociceptive effect of each opioid agonist was evaluated after intracerebroventricular (i.c.v.) or intravenous administration (i.v.) of the peptides. Circular dichroism methods and high-field nuclear magnetic resonance were used in the presence and absence of sodium dodecylsulfate to understand how the presence of a membrane might influence the peptide conformations.

Original languageEnglish (US)
Pages (from-to)749-756
Number of pages8
JournalChemical Biology and Drug Design
Issue number5
StatePublished - Nov 2011


  • Circular dichroism
  • Drug delivery/ADMET
  • Nuclear magnetic resonance
  • Peptide
  • Phosphate

ASJC Scopus subject areas

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


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