title: Can amphipathic helices influence the CNS antinociceptive activity of glycopeptides related to β-endorphin?
abstract: 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 K(i)'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.
authors.affiliation: Department of Chemistry & Biochemistry and BIO5, The University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Yingxue
authors.initials: Y
authors.lastname: Li
authors.forename: Lindsay
authors.initials: L
authors.lastname: St Louis
authors.forename: Brian I
authors.initials: BI
authors.lastname: Knapp
authors.forename: Dhanasekaran
authors.initials: D
authors.lastname: Muthu
authors.forename: Bobbi
authors.initials: B
authors.lastname: Anglin
authors.forename: Denise
authors.initials: D
authors.lastname: Giuvelis
authors.forename: Jean M
authors.initials: JM
authors.lastname: Bidlack
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Bilsky
authors.forename: Robin
authors.initials: R
authors.lastname: Polt
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002942:Circular Dichroism; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006020:Glycopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008823:Micelles; D008958:Models, Molecular; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013329:Structure-Activity Relationship; D001615:beta-Endorphin / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D006020:Glycopeptides; D008823:Micelles; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D001615:beta-Endorphin