Karel Guillemyn 1 , Joanna Starnowska 2 , Camille Lagard 3 , Jolanta Dyniewicz 4 , Ewelina Rojewska 2 , Joanna Mika 2 , Nga N Chung 5 , Valérie Utard 6 , Piotr Kosson 4 , Andrzej W Lipkowski 4 , Lucie Chevillard 3 , Pol Arranz-Gibert 7 , Meritxell Teixidó 7 , Bruno Megarbane 3 , Dirk Tourwé 1 , Frédéric Simonin 6 , Barbara Przewlocka 2 , Peter W Schiller 5 , Steven Ballet 1
Apr 28 2016
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.