Nociceptin /Orphanin FQ Peptide” receptor (NOPr) is a G-protein-coupled receptor
with the nociceptin/orphanin FQ peptide (N/OFQ) as endogenous agonist. It is expressed
in the nervous system as well as in some non-neural tissues. Its activation has
pronociceptive effect at the supraspinal level, whereas at the spinal level it produces nociceptive
effects at low doses and antinociceptive effects at higher doses. NOPr is also involved
in mood and blood pressure regulation, immunoregulation, airway constriction,
feeding, urination, bowel motility, learning and memory. Selective NOPr agonists have
been tested clinically as anxiolytics and antitussives, and the antagonists as analgesics, antidepressants
and in the treatment of alcohol addiction. Two NOPr radioligands have also
been tested in humans as neuroimaging agents. Furthermore, the partial agonist peptide
SER100 and N/OFQ have been used in clinical trials, respectively for congestive heart
failure and overactive bladder. The evidence of interactions between NOP and μ-opioid
receptor (MOPr) receptors has been exploited in the use of mixed NOPr/MOPr modulators
as analgesics and in the treatment of drug addiction. These drugs are devoid of typical
opioid liabilities. In this review, we outline the latest advances in the structure-activity relationships
(SAR) of NOPr agonists and antagonists, with emphasis on affinity, activity,
selectivity and pharmacokinetic features.