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Chem Biol Drug Des. 2011 Nov;78(5):749-56. doi: 10.1111/j.1747-0285.2011.01203.x. Epub 2011 Sep 26.

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

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  • 1Carl S. Marvel Laboratories, Department of Chemistry and Biochemistry, BIO5, The University of Arizona, Tucson, AZ 85721, USA.


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.

© 2011 John Wiley & Sons A/S.

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