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