1. Can amphipathic helices influence the CNS antinociceptive activity of glycopeptides related to β-endorphin?
- Author
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Li Y, St Louis L, Knapp BI, Muthu D, Anglin B, Giuvelis D, Bidlack JM, Bilsky EJ, and Polt R
- Subjects
- Animals, CHO Cells, Circular Dichroism, Cricetinae, Cricetulus, Drug Design, Glycopeptides chemical synthesis, Humans, Injections, Intravenous, Injections, Intraventricular, Magnetic Resonance Spectroscopy, Male, Mice, Micelles, Models, Molecular, Protein Conformation, Protein Structure, Secondary, Receptors, Opioid, delta metabolism, Receptors, Opioid, kappa drug effects, Receptors, Opioid, mu metabolism, Structure-Activity Relationship, Analgesics chemical synthesis, Analgesics pharmacology, Glycopeptides chemistry, Glycopeptides pharmacology, beta-Endorphin analogs & derivatives, beta-Endorphin pharmacology
- 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.
- Published
- 2014
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