Development of a peptidomimetic antagonist of neuropeptide FF receptors for the prevention of opioid-induced hyperalgesia

ACS Chem Neurosci. 2015 Mar 18;6(3):438-45. doi: 10.1021/cn500219h. Epub 2015 Feb 7.

Abstract

Through the development of a new class of unnatural ornithine derivatives as bioisosteres of arginine, we have designed an orally active peptidomimetic antagonist of neuropeptide FF receptors (NPFFR). Systemic low-dose administration of this compound to rats blocked opioid-induced hyperalgesia, without any apparent side-effects. Interestingly, we also observed that this compound potentiated opioid-induced analgesia. This unnatural ornithine derivative provides a novel therapeutic approach for both improving analgesia and reducing hyperalgesia induced by opioids in patients being treated for chronic pain.

Keywords: GPCR; GPR147; GPR74; NPFF; arginine; bioisoster; opioid-induced hyperalgesia; ornithine; peptidomimetic; unnatural amino acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / toxicity*
  • Animals
  • Arginine / metabolism
  • Chemical Phenomena
  • Cyclic AMP / metabolism
  • Fentanyl / toxicity*
  • HEK293 Cells
  • Humans
  • Hyperalgesia / chemically induced*
  • Hyperalgesia / prevention & control*
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Ornithine / metabolism
  • Pain Threshold / drug effects
  • Peptidomimetics / chemistry
  • Peptidomimetics / therapeutic use*
  • Protein Binding / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Neuropeptide / antagonists & inhibitors
  • Receptors, Neuropeptide / metabolism
  • Structure-Activity Relationship
  • Time Factors
  • Tritium / pharmacokinetics

Substances

  • Analgesics, Opioid
  • Peptidomimetics
  • Receptors, Neuropeptide
  • neuropeptide FF receptor
  • Tritium
  • Arginine
  • Cyclic AMP
  • Ornithine
  • Fentanyl