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J Med Chem. 2016 Apr 28;59(8):3777-92. doi: 10.1021/acs.jmedchem.5b01976. Epub 2016 Apr 14.

Bifunctional Peptide-Based Opioid Agonist-Nociceptin Antagonist Ligands for Dual Treatment of Acute and Neuropathic Pain.

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Research Group of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel , Pleinlaan 2, 1050 Brussels, Belgium.
Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences , Smetna 12, PL 31-343 Kraków, Poland.
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.
Neuropeptide Laboratory, Medical Research Centre, Polish Academy of Sciences , 5 Pawinskiego Street, PL 02-106 Warsaw, Poland.
Department of Chemical Biology and Peptide Research, Clinical Research Institute , 110 Avenue Des Pins Ouest, Montreal, Quebec H2W 1R7, Canada.
University of Strasbourg, CNRS, UMR7242, ESBS , 67412 Illkirch-Graffenstaden, France.
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST) , Baldiri Reixac 10, 08028 Barcelona, Spain.


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.

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