Medicinal Chemistry, Pharmacology, and Biological Actions of Peptide Ligands Selective for the Nociceptin/Orphanin FQ Receptor

Nociceptin/orphanin FQ (N/OFQ; FGGFTGARKSARKLANQ) was identified via reverse pharmacology strategies as the endogenous ligand of a previously orphan GPCR now referred to as N/OFQ peptide (NOP) receptor. The N/OFQ – NOP receptor system is widely distributed in the nervous system where it modulates several different biological functions. Structure relationship studies performed on the N/OFQ sequence allowed to generate NOP selective ligands encompassing full and partial agonist as well as pure antagonist activity, to increase their potency, metabolic stability, and in vivo duration of action. These peptide NOP ligands were used to investigate the consequences of NOP receptor activation and block thus suggesting the possible therapeutic indications of drugs interacting with this receptor. Evidence coming from these studies, together with findings obtained with knockout animals and non peptide NOP ligands, suggests that the most promising indications for NOP antagonists are depression and Parkinson disease and for agonists anxiety, drug abuse, cough, and pain (after spinal administration). In addition, clinical studies demonstrated that intravesical instillation of N/OFQ elicits beneficial effects in patients with overactive bladder.