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.

Transmission pathways and mediators as the basis for clinical pharmacology of pain

“…Recently, hybrid molecules have been developed to take advantage of these dimers with the aim of improving opioid pain control. In one study, a hybrid was made from an opioid pharmacophore and an NOP ligand [53]. When compared directly to morphine, this hybrid showed later onset of action, but longer acting pain relief in a rodent pain model [53].…”

“…In one study, a hybrid was made from an opioid pharmacophore and an NOP ligand [53]. When compared directly to morphine, this hybrid showed later onset of action, but longer acting pain relief in a rodent pain model [53]. Opioid receptor dimers and associated hybrids provide a new area within opioid pain research.…”

Biochemical, functional and pharmacological characterization of novel bifunctional peptide ligands and nociceptin variants

“…Ac-RYYRIK-NH2 was in the focus of interest several times when MOP/NOP and other OP/NOP receptor bivalent ligands were developed. These bivalent ligands were designed to study the heterodimerization of opioid and NOP receptors and to develop new therapeutic agents [85][86][87][88][89] .…”

“…Ac-RYYRIK-NH2 was in the focus of interest several times when MOP/NOP and other OP/NOP receptor bivalent ligands were developed. These bivalent ligands were designed to study the heterodimerization of opioid and NOP receptors, namely, the organization of the heterodimers; to develop new therapeutic agents, and to reduce morphine-related side effects 86 . Intravenous 13a has a more prolonged effect than morphine.…”

“…Intrathecally it had superior anti-allodynic and antihyperalgesic properties than either morphine or Ac-RYYRIK-NH2. Overall, this ligand can be already effective at nanomolar concentrations and may be useful for both acute and neuropathic pain 86 .…”