Can amphipathic helices influence the CNS antinociceptive activity of glycopeptides related to β-endorphin?

Yingxue Li, Lindsay St. Louis, Brian I. Knapp, Dhanasekaran Muthu, Bobbi Anglin, Denise Giuvelis, Jean M. Bidlack, Edward J. Bilsky, Robin L Polt

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Glycosylated β-endorphin analogues of various amphipathicity were studied in vitro and in vivo in mice. Opioid binding affinities of the O-linked glycopeptides (mono- or disaccharides) and unglycosylated peptide controls were measured in human receptors expressed in CHO cells. All were pan-agonists, binding to μ-, δ-, or κ-opioid receptors in the low nanomolar range (2.2-35 nM Ki's). The glycoside moiety was required for intravenous (i.v.) but not for intracerebroventricular (i.c.v.) activity. Circular dichroism and NMR indicated the degree of helicity in H2O, aqueous trifluoroethanol, or micelles. Glycosylation was essential for activity after i.v. administration. It was possible to manipulate the degree of helicity by the alteration of only two amino acid residues in the helical address region of the β-endorphin analogues without destroying μ-, δ-, or κ-agonism, but the antinociceptive activity after i.v. administration could not be directly correlated to the degree of helicity in micelles.

Original languageEnglish (US)
Pages (from-to)2237-2246
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number6
Publication statusPublished - Mar 27 2014


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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