Structure-Activity Relationships of Nociceptin Receptor (NOP) Ligands and the Design of Bifunctional NOP/Mu Opioid Receptor-Targeted Ligands

The nociceptin receptor NOP, the fourth member of the opioid receptor family, continues to be of significant interest as a target for therapeutic applications in the treatment of drug dependence, anxiety, and pain, to name a few. Its endogenous ligand, a heptadecapeptide nociceptin/orphanin FQ (N/OFQ) has pharmacological actions distinct from the classical opioid peptides, and has been shown to modulate opioid actions in many neurological circuits. Over the past decade, several nonpeptide (small-molecule) and peptide NOP ligands have been reported both by industry as well as academic laboratories, including our own. NOP agonists as well as NOP antagonists have been reported. The recent resolution of the ‘antagonist’ bound crystal structure of the NOP receptor and our recent report of the active-state homology model of the NOP receptor will facilitate our understanding of the structure-activity relationships (SAR) of NOP antagonists and agonists respectively. This review presents a ligand and structure-based assessment of the SAR for potent NOP binding pharmacophores. This review also presents rational approaches for designing ‘bifunctional’ NOP/opioid ligands, which have equipotent affinity for the NOP and mu opioid receptors and the desired functional profile of NOP agonist and mu opioid agonist activity. Such bifunctional NOP/mu agonists may have utility as non-addicting analgesics and drug abuse treatment with lower propensity of withdrawal-related effects.