The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential

Nociceptin/orphanin FQ (N/OFQ) is the first example of a peptide that was isolated by reverse pharmacology.N/OFQ activates a Gi-protein-coupled receptor, NOP, and this peptide–receptor system has been implicated in a diverse range of biological functions including (but not limited to) pain, reward/drug abuse, cardiovascular control and immune function.Many peptide and non-peptide ligands are available. The main chemical classes of the current non-peptides are morphinans (for example, buprenorphine; mixed); aminoquinolines (for example, JTC-801; antagonist); benzimidazopiperidines (for example, J-113397; antagonist); aryl-piperidines (for example, SB-612111; antagonist); and spiropiperidines (for example, Ro64-6198; agonist).Central NOP antagonists have, variably, antinociceptive (supraspinal), and antidepressant effects. Central NOP agonists have anti-opioid (supraspinal), antinociceptive (spinal), anxiolytic effects and produce bradycardia/hypotension.Peripheral NOP agonists have antinociceptive, vasodilatory and aquaretic effects. They also produce bardycardia and hypotension, and inhibit bladder activity.A small number of molecules are in clinical development: ZP120, a peptide in Phase I and II for congestive heart failure, and JTC-801, a non-peptide antagonist in Phase II for pain.