Nociceptin Opioid Receptor (NOP) as a Therapeutic Target: Progress in Translation from Preclinical Research to Clinical Utility

Abstract

In the two decades since the discovery of the nociceptin opioid receptor (NOP) and its ligand, nociceptin/orphaninFQ (N/OFQ), steady progress has been achieved in understanding the pharmacology of this fourth opioid receptor/peptide system, aided by genetic and pharmacologic approaches. This research spawned an explosion of small-molecule NOP receptor ligands from discovery programs in major pharmaceutical companies. NOP agonists have been investigated for their efficacy in preclinical models of anxiety, cough, substance abuse, pain (spinal and peripheral), and urinary incontinence, whereas NOP antagonists have been investigated for treatment of pain, depression, and motor symptoms in Parkinson's disease. Translation of preclinical findings into the clinic is guided by PET and receptor occupancy studies, particularly for NOP antagonists. Recent progress in preclinical NOP research suggests that NOP agonists may have clinical utility for pain treatment and substance abuse pharmacotherapy. This review discusses the progress toward validating the NOP-N/OFQ system as a therapeutic target.

Figure 1

Structures and in vitro pharmacological profiles of known NOP agonists. Note that the in vitro data from the cited references are from different laboratories and use different radioligands and protocols for the assays, and therefore cannot be directly compared.

Figure 2

Structures and in vitro pharmacological profiles of NOP antagonists widely used as tool compounds. Note that the in vitro data from the cited references are from different laboratories and use different radioligands and protocols for the assays, and therefore cannot be directly compared.

Figure 3

Structures and in vitro pharmacological profiles of NOP antagonist-based PET tracers and radioligands recently developed for the NOP receptor.