title: Development of a peptidomimetic antagonist of neuropeptide FF receptors for the prevention of opioid-induced hyperalgesia.
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.
authors.affiliation: †University of Strasbourg, CNRS, UMR7200, Faculty of pharmacy, 67400 Illkirch Graffenstaden, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bihel
authors.affiliation: ‡University of Strasbourg, CNRS, UMR7242, ESBS, 67412 Illkirch Graffenstaden, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Humbert
authors.affiliation: †University of Strasbourg, CNRS, UMR7200, Faculty of pharmacy, 67400 Illkirch Graffenstaden, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Schneider
authors.affiliation: ‡University of Strasbourg, CNRS, UMR7242, ESBS, 67412 Illkirch Graffenstaden, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bertin
authors.affiliation: †University of Strasbourg, CNRS, UMR7200, Faculty of pharmacy, 67400 Illkirch Graffenstaden, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Wagner
authors.affiliation: †University of Strasbourg, CNRS, UMR7200, Faculty of pharmacy, 67400 Illkirch Graffenstaden, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Schmitt
authors.affiliation: §University of Bordeaux Ségalen, INCIA, CNRS UMR5287, 33076 Bordeaux, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Laboureyras
authors.affiliation: ∥Institut Clinique de la Souris, University of Strasbourg, 67404 Illkirch, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Petit-Demoulière
authors.affiliation: ⊥Phenopro, 67400 Illkirch, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Schneider
authors.affiliation: #University of Toulouse, CNRS, UMR5089, IPBS, 31077 Toulouse, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Mollereau
authors.affiliation: §University of Bordeaux Ségalen, INCIA, CNRS UMR5287, 33076 Bordeaux, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Simonnet
authors.affiliation: ‡University of Strasbourg, CNRS, UMR7242, ESBS, 67412 Illkirch Graffenstaden, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Simonin
authors.affiliation: †University of Strasbourg, CNRS, UMR7200, Faculty of pharmacy, 67400 Illkirch Graffenstaden, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Bourguignon
mesh_terms: D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D001120:Arginine / Q000378:metabolism; D055598:Chemical Phenomena; D000242:Cyclic AMP / Q000378:metabolism; D005283:Fentanyl / Q000633:toxicity*; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009952:Ornithine / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects; D057786:Peptidomimetics / Q000737:chemistry / Q000627:therapeutic use*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D000701:Analgesics, Opioid; D057786:Peptidomimetics; D018013:Receptors, Neuropeptide; C083929:neuropeptide FF receptor; D014316:Tritium; D001120:Arginine; D000242:Cyclic AMP; D009952:Ornithine; D005283:Fentanyl
keywords: GPCR; GPR147; GPR74; NPFF; arginine; bioisoster; opioid-induced hyperalgesia; ornithine; peptidomimetic; unnatural amino acid