Potent, Efficacious, and Stable Cyclic Opioid Peptides with Long Lasting Antinociceptive Effect after Peripheral Administration

J Med Chem. 2020 Mar 12;63(5):2673-2687. doi: 10.1021/acs.jmedchem.9b01963. Epub 2019 Dec 27.

Abstract

Four novel fluorinated cyclic analogues of biphalin with excellent to modest binding affinity for μ-, δ-, and κ-receptors were synthesized. The cyclic peptides have a combination of piperazine or hydrazine linker with or without a xylene bridge. Among the ligands, MACE3 demonstrated a better activity than biphalin after intravenous administration, and its corresponding analogue incorporating the hydrazine linker (MACE2) was able to induce longer lasting analgesia following subcutaneous administration. An analogue of MACE2 containing 2,6-dimethyl-l-tyrosine (MACE4) showed the best potency and in vivo antinociceptive activity of this series.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / pharmacokinetics
  • Analgesics, Opioid / pharmacology
  • Analgesics, Opioid / therapeutic use*
  • Animals
  • CHO Cells
  • Cricetulus
  • Female
  • Humans
  • Infusions, Subcutaneous
  • Male
  • Mice
  • Models, Molecular
  • Opioid Peptides / administration & dosage
  • Opioid Peptides / pharmacokinetics
  • Opioid Peptides / pharmacology
  • Opioid Peptides / therapeutic use*
  • Pain / drug therapy*
  • Pain / metabolism
  • Peptides, Cyclic / administration & dosage
  • Peptides, Cyclic / pharmacokinetics
  • Peptides, Cyclic / pharmacology
  • Peptides, Cyclic / therapeutic use*
  • Receptors, Opioid / metabolism

Substances

  • Analgesics, Opioid
  • Opioid Peptides
  • Peptides, Cyclic
  • Receptors, Opioid