title: Bifunctional Peptide-Based Opioid Agonist-Nociceptin Antagonist Ligands for Dual Treatment of Acute and Neuropathic Pain.
abstract: Herein, the opioid pharmacophore H-Dmt-d-Arg-Aba-β-Ala-NH2 (7) was linked to peptide ligands for the nociceptin receptor. Combination of 7 and NOP ligands (e.g., H-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) led to binding affinities in the low nanomolar domain. In vitro, the hybrids behaved as agonists at the opioid receptors and antagonists at the nociceptin receptor. Intravenous administration of hybrid 13a (H-Dmt-d-Arg-Aba-β-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) to mice resulted in potent and long lasting antinociception in the tail-flick test, indicating that 13a was able to permeate the BBB. This was further supported by a cell-based BBB model. All hybrids alleviated allodynia and hyperalgesia in neuropathic pain models. Especially with respect to hyperalgesia, they showed to be more effective than the parent compounds. Hybrid 13a did not result in significant respiratory depression, in contrast to an equipotent analgesic dose of morphine. These hybrids hence represent a promising avenue toward analgesics for the dual treatment of acute and neuropathic pain.
authors.affiliation: Research Group of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel , Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: Guillemyn
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences , Smetna 12, PL 31-343 Kraków, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Starnowska
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Réanimation Médicale et Toxicologique, Inserm U1144, Université Paris Descartes UMR-S 1144, Université Paris Didero, UMR-S 1144 , Paris, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Lagard
authors.affiliation: Neuropeptide Laboratory, Medical Research Centre, Polish Academy of Sciences , 5 Pawinskiego Street, PL 02-106 Warsaw, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Dyniewicz
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences , Smetna 12, PL 31-343 Kraków, Poland.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Rojewska
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences , Smetna 12, PL 31-343 Kraków, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Mika
authors.affiliation: Department of Chemical Biology and Peptide Research, Clinical Research Institute , 110 Avenue Des Pins Ouest, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Nga N
authors.initials: NN
authors.lastname: Chung
authors.affiliation: University of Strasbourg, CNRS, UMR7242, ESBS , 67412 Illkirch-Graffenstaden, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Utard
authors.affiliation: Neuropeptide Laboratory, Medical Research Centre, Polish Academy of Sciences , 5 Pawinskiego Street, PL 02-106 Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Kosson
authors.affiliation: Neuropeptide Laboratory, Medical Research Centre, Polish Academy of Sciences , 5 Pawinskiego Street, PL 02-106 Warsaw, Poland.
authors.forename: Andrzej W
authors.initials: AW
authors.lastname: Lipkowski
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Réanimation Médicale et Toxicologique, Inserm U1144, Université Paris Descartes UMR-S 1144, Université Paris Didero, UMR-S 1144 , Paris, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Chevillard
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST) , Baldiri Reixac 10, 08028 Barcelona, Spain.
authors.forename: Pol
authors.initials: P
authors.lastname: Arranz-Gibert
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST) , Baldiri Reixac 10, 08028 Barcelona, Spain.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Teixidó
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Réanimation Médicale et Toxicologique, Inserm U1144, Université Paris Descartes UMR-S 1144, Université Paris Didero, UMR-S 1144 , Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Megarbane
authors.affiliation: Research Group of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel , Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Tourwé
authors.affiliation: University of Strasbourg, CNRS, UMR7242, ESBS , 67412 Illkirch-Graffenstaden, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Simonin
authors.affiliation: Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences , Smetna 12, PL 31-343 Kraków, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Przewlocka
authors.affiliation: Department of Chemical Biology and Peptide Research, Clinical Research Institute , 110 Avenue Des Pins Ouest, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Schiller
authors.affiliation: Research Group of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel , Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Ballet
mesh_terms: D000208:Acute Disease; D000595:Amino Acid Sequence; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier; D002463:Cell Membrane Permeability / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009437:Neuralgia / Q000188:drug therapy*; D059408:Pain Management / Q000379:methods*; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000187:drug effects*; D000094942:Nociceptin Receptor
chemical_list: D008024:Ligands; D009292:Narcotic Antagonists; D010455:Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor