Phosphorylation of enkephalins

NMR and CD studies in aqueous and membrane-mimicking environments

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

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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
Volume78
Issue number5
DOIs
StatePublished - Nov 2011

Fingerprint

Phosphorylation
Enkephalins
Nuclear magnetic resonance
Membranes
Peptides
Biological Availability
Ala(2)-MePhe(4)-Gly(5)-enkephalin
Glycosylation
Glucosides
Opioid Receptors
Circular Dichroism
Cricetulus
Blood-Brain Barrier
Intravenous Administration
Serine
Opioid Analgesics
Conformations
Tail
Ovary
Permeability

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Phosphorylation of enkephalins : NMR and CD studies in aqueous and membrane-mimicking environments. / Yeomans, Larisa; Muthu, Dhanasekaran; Lowery, John J.; Martinez, Heather N.; Abrell, Leif M; Lin, Guanxin; Strom, Kyle; Knapp, Brian I.; Bidlack, Jean M.; Bilsky, Edward J.; Polt, Robin L.

In: Chemical Biology and Drug Design, Vol. 78, No. 5, 11.2011, p. 749-756.

Research output: Contribution to journalArticle

Yeomans, L, Muthu, D, Lowery, JJ, Martinez, HN, Abrell, LM, Lin, G, Strom, K, Knapp, BI, Bidlack, JM, Bilsky, EJ & Polt, RL 2011, 'Phosphorylation of enkephalins: NMR and CD studies in aqueous and membrane-mimicking environments', Chemical Biology and Drug Design, vol. 78, no. 5, pp. 749-756. https://doi.org/10.1111/j.1747-0285.2011.01203.x
Yeomans, Larisa ; Muthu, Dhanasekaran ; Lowery, John J. ; Martinez, Heather N. ; Abrell, Leif M ; Lin, Guanxin ; Strom, Kyle ; Knapp, Brian I. ; Bidlack, Jean M. ; Bilsky, Edward J. ; Polt, Robin L. / Phosphorylation of enkephalins : NMR and CD studies in aqueous and membrane-mimicking environments. In: Chemical Biology and Drug Design. 2011 ; Vol. 78, No. 5. pp. 749-756.
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