Structural Requirements for CNS Active Opioid Glycopeptides

Mark Lefever, Yingxue Li, Bobbi Anglin, Dhanasekaran Muthu, Denise Giuvelis, John J. Lowery, Brian I. Knapp, Jean M. Bidlack, Edward J. Bilsky, Robin Polt

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Glycopeptides related to β-endorphin penetrate the blood-brain barrier (BBB) of mice to produce antinociception. Two series of glycopeptides were assessed for opioid receptor binding affinity. Attempts to alter the mu-selectivity of [d-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAMGO)-related glycopeptides by altering the charged residues of the amphipathic helical address were unsuccessful. A series of pan-agonists was evaluated for antinociceptive activity (55 °C tail flick) in mice. A flexible linker was required to maintain antinociceptive activity. Circular dichroism (CD) in H2O, trifluoroethanol (TFE), and SDS micelles confirmed the importance of the amphipathic helices (11s → 11sG → 11) for antinociception. The glycosylated analogues showed only nascent helices and random coil conformations in H2O. Chemical shift indices (CSI) and nuclear Overhauser effects (NOE) with 600 MHz NMR and CD confirmed helical structures in micelles, which were rationalized by molecular dynamics calculations. Antinociceptive studies with mice confirm that these glycosylated endorphin analogues are potential drug candidates that penetrate the BBB to produce potent central effects.

Original languageEnglish (US)
Pages (from-to)5728-5741
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number15
StatePublished - Jun 30 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


Dive into the research topics of 'Structural Requirements for CNS Active Opioid Glycopeptides'. Together they form a unique fingerprint.

Cite this