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

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.