Activities of mixed NOP and mu-opioid receptor ligands.

Background and purpose:Compounds that activate both NOP and mu-opioid receptors might be useful as analgesics and drug abuse medications. Studies were carried out to better understand the biological activity of such compounds.Experimental approach:Binding affinities were determined on membranes from cells transfected with NOP and opioid receptors. Functional activity was determined by [(35)S]GTPgammaS binding on cell membranes and using the mouse vas deferens preparation in vitro and the tail flick antinociception assay in vivo.Key results:Compounds ranged in affinity from SR14150, 20-fold selective for NOP receptors, to buprenorphine, 50-fold selective for mu-opioid receptors. In the [(35)S]GTPgammaS assay, SR compounds ranged from full agonist to antagonist at NOP receptors and most were partial agonists at mu-opioid receptors. Buprenorphine was a low efficacy partial agonist at mu-opioid receptors, but did not stimulate [(35)S]GTPgammaS binding through NOP. In the mouse vas deferens, each compound, except for SR16430, inhibited electrically induced contractions. In each case, except for N/OFQ itself, the inhibition was due to mu-opioid receptor activation, as determined by equivalent results in NOP receptor knockout tissues. SR14150 showed antinociceptive activity in the tail flick test, which was reversed by the opioid antagonist naloxone.Conclusions and implications:Compounds that bind to both mu-opioid and NOP receptors have antinociceptive activity but the relative contribution of each receptor is unclear. These experiments help characterize compounds that bind to both receptors, to better understand the mechanism behind their biological activities, and identify new pharmacological tools to characterize NOP and opioid receptors

Activities of mixed NOP and mu-opioid receptor ligands

Background and purpose:Compounds that activate both NOP and mu-opioid receptors might be useful as analgesics and drug abuse medications. Studies were carried out to better understand the biological activity of such compounds.Experimental approach:Binding affinities were determined on membranes from cells transfected with NOP and opioid receptors. Functional activity was determined by [(35)S]GTPgammaS binding on cell membranes and using the mouse vas deferens preparation in vitro and the tail flick antinociception assay in vivo.Key results:Compounds ranged in affinity from SR14150, 20-fold selective for NOP receptors, to buprenorphine, 50-fold selective for mu-opioid receptors. In the [(35)S]GTPgammaS assay, SR compounds ranged from full agonist to antagonist at NOP receptors and most were partial agonists at mu-opioid receptors. Buprenorphine was a low efficacy partial agonist at mu-opioid receptors, but did not stimulate [(35)S]GTPgammaS binding through NOP. In the mouse vas deferens, each compound, except for SR16430, inhibited electrically induced contractions. In each case, except for N/OFQ itself, the inhibition was due to mu-opioid receptor activation, as determined by equivalent results in NOP receptor knockout tissues. SR14150 showed antinociceptive activity in the tail flick test, which was reversed by the opioid antagonist naloxone.Conclusions and implications:Compounds that bind to both mu-opioid and NOP receptors have antinociceptive activity but the relative contribution of each receptor is unclear. These experiments help characterize compounds that bind to both receptors, to better understand the mechanism behind their biological activities, and identify new pharmacological tools to characterize NOP and opioid receptors

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