title: Structural Requirements for CNS Active Opioid Glycopeptides.
abstract: 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-Ala(2),N-MePhe(4),Gly-ol(5)]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.
authors.affiliation: †Carl S. Marvel Laboratories, Department of Chemistry and Biochemistry, BIO5, The University of Arizona, Tucson, Arizona 85721, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Lefever
authors.affiliation: †Carl S. Marvel Laboratories, Department of Chemistry and Biochemistry, BIO5, The University of Arizona, Tucson, Arizona 85721, United States.
authors.forename: Yingxue
authors.initials: Y
authors.lastname: Li
authors.affiliation: †Carl S. Marvel Laboratories, Department of Chemistry and Biochemistry, BIO5, The University of Arizona, Tucson, Arizona 85721, United States.
authors.forename: Bobbi
authors.initials: B
authors.lastname: Anglin
authors.affiliation: †Carl S. Marvel Laboratories, Department of Chemistry and Biochemistry, BIO5, The University of Arizona, Tucson, Arizona 85721, United States.
authors.forename: Dhanasekaran
authors.initials: D
authors.lastname: Muthu
authors.affiliation: §Department of Biomedical Sciences, COM and Center for Excellence in the Neurosciences, University of New England, 11 Hills Beach Road, Biddeford, Maine 04005, United States.
authors.forename: Denise
authors.initials: D
authors.lastname: Giuvelis
authors.affiliation: §Department of Biomedical Sciences, COM and Center for Excellence in the Neurosciences, University of New England, 11 Hills Beach Road, Biddeford, Maine 04005, United States.
authors.forename: John J
authors.initials: JJ
authors.lastname: Lowery
authors.affiliation: ‡Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642-8711, United States.
authors.forename: Brian I
authors.initials: BI
authors.lastname: Knapp
authors.affiliation: ‡Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642-8711, United States.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Bidlack
authors.affiliation: §Department of Biomedical Sciences, COM and Center for Excellence in the Neurosciences, University of New England, 11 Hills Beach Road, Biddeford, Maine 04005, United States.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Bilsky
authors.affiliation: †Carl S. Marvel Laboratories, Department of Chemistry and Biochemistry, BIO5, The University of Arizona, Tucson, Arizona 85721, United States.
authors.forename: Robin
authors.initials: R
authors.lastname: Polt
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects*; D002942:Circular Dichroism; D006020:Glycopeptides / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018847:Opioid Peptides / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D017450:Receptors, Opioid, mu / Q000187:drug effects
chemical_list: D006020:Glycopeptides; D018847:Opioid Peptides; D017450:Receptors, Opioid, mu