Improving metabolic stability by glycosylation: bifunctional peptide derivatives that are opioid receptor agonists and neurokinin 1 receptor antagonists

J Med Chem. 2009 Aug 27;52(16):5164-75. doi: 10.1021/jm900473p.

Abstract

In order to obtain a metabolically more stable analgesic peptide derivative, O-beta-glycosylated serine (Ser(Glc)) was introduced into TY027 (Tyr-d-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-3',5'-Bzl(CF(3))(2)) which was a previously reported bifunctional compound with delta/micro opioid agonist and neurokinin-1 receptor antagonist activities and with a half-life of 4.8 h in rat plasma. Incorporation of Ser(Glc) into various positions of TY027 gave analogues with variable bioactivities. Analogue 6 (Tyr-d-Ala-Gly-Phe-Nle-Pro-Leu-Ser(Glc)-Trp-NH-3',5'-Bzl(CF(3))(2)) was found to have effective bifunctional activities with a well-defined conformation with two beta-turns based on the NMR conformational analysis in the presence of DPC micelles. In addition, 6 showed significant improvement in its metabolic stability (70 + or - 9% of 6 was intact after 24 h incubation in rat plasma). This improved metabolic stability, along with its effective and delta selective bifunctional activities, suggests that 6 could be an interesting research tool and possibly a promising candidate as a novel analgesic drug.

Publication types

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

MeSH terms

  • Analgesics / blood
  • Analgesics / chemical synthesis*
  • Analgesics / pharmacology
  • Animals
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cricetinae
  • Cricetulus
  • Glycosylation
  • Guinea Pigs
  • Hydrogen Bonding
  • Ileum / drug effects
  • Ileum / physiology
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Male
  • Mice
  • Models, Molecular
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology
  • Neurokinin-1 Receptor Antagonists*
  • Oligopeptides / blood
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / pharmacology
  • Protein Structure, Secondary
  • Radioligand Assay
  • Rats
  • Receptors, Neurokinin-1 / metabolism
  • Receptors, Opioid, delta / agonists*
  • Receptors, Opioid, delta / metabolism
  • Receptors, Opioid, mu / agonists*
  • Structure-Activity Relationship
  • Vas Deferens / drug effects
  • Vas Deferens / physiology

Substances

  • Analgesics
  • Ligands
  • Neurokinin-1 Receptor Antagonists
  • Oligopeptides
  • Receptors, Neurokinin-1
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • Tyr-D-Ala-Gly-Phe-Nle-Pro-Leu-Ser(Glc)-Trp-NH-3',5'-Bzl(CF3)2