title: Development of a bioavailable μ opioid receptor (MOPr) agonist, δ opioid receptor (DOPr) antagonist peptide that evokes antinociception without development of acute tolerance.
abstract: We have previously described a cyclic tetrapeptide, 1, that displays μ opioid receptor (MOPr) agonist and δ opioid receptor (DOPr) antagonist activity, a profile associated with a reduced incidence of opioid tolerance and dependence. Like many peptides, 1 has poor bioavailability. We describe here an analogue of 1 with an added C-terminal β-glucosylserine residue, Ser(β-Glc)NH2, a modification that has previously been shown to improve bioavailability of opioid peptides. The resulting peptide, 4, exhibits full antinociceptive efficacy in the mouse warm water tail withdrawal assay after intraperitoneal administration with potency similar to that of morphine. Further, 4 does not give rise to acute tolerance and thus represents a promising lead for the development of opioid analgesics with reduced side effects.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Henry I
authors.initials: HI
authors.lastname: Mosberg
authors.forename: Larisa
authors.initials: L
authors.lastname: Yeomans
authors.forename: Jessica P
authors.initials: JP
authors.lastname: Anand
authors.forename: Vanessa
authors.initials: V
authors.lastname: Porter
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Sobczyk-Kojiro
authors.forename: John R
authors.initials: JR
authors.lastname: Traynor
authors.forename: Emily M
authors.initials: EM
authors.lastname: Jutkiewicz
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D004361:Drug Tolerance; D005260:Female; D005910:Glioma / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009292:Narcotic Antagonists / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D000700:Analgesics; D009292:Narcotic Antagonists; D010446:Peptide Fragments; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu