Development of a bioavailable μ opioid receptor (MOPr) agonist, δ opioid receptor (DOPr) antagonist peptide that evokes antinociception without development of acute tolerance

J Med Chem. 2014 Apr 10;57(7):3148-53. doi: 10.1021/jm5002088. Epub 2014 Mar 26.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analgesics / pharmacology*
  • Animals
  • Biological Availability
  • Drug Tolerance*
  • Female
  • Glioma / drug therapy
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Narcotic Antagonists / pharmacology*
  • Pain / drug therapy*
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology*
  • Radioligand Assay
  • Rats
  • Receptors, Opioid, delta / antagonists & inhibitors*
  • Receptors, Opioid, mu / antagonists & inhibitors*
  • Tumor Cells, Cultured

Substances

  • Analgesics
  • Narcotic Antagonists
  • Peptide Fragments
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu