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NEUROPHARMACOLOGY

[(pF)Phe⁴,Arg¹⁴,Lys¹⁵]N/OFQ-NH₂ (UFP-102), a Highly Potent and Selective Agonist of the Nociceptin/Orphanin FQ Receptor

Department of Experimental and Clinical Medicine, Section of Pharmacology and Neuroscience Center (G.C., A.R., F.M., G.M., D.R., E.G., S.Z., D.R., M.M., G.C.) and Department of Pharmaceutical Sciences and Biotechnology Center (R.G., S.S.), University of Ferrara, Ferrara, Italy; Department of Cardiovascular Sciences, Pharmacology and Therapeutics Group (T.A.B., J.M., C.P.H., D.G.L.) and Department of Health Sciences, Division of Anaesthesia, Critical Care and Pain Management (D.J.R.), Leicester Royal Infirmary, Leicester, United Kingdom; and Department of Pharmacology (V.A.K., D.R.K.), Louisiana State University, Health Sciences Center, New Orleans, Louisiana

A novel ligand for the nociceptin/orphanin FQ (N/OFQ) receptor (NOP), [(pF)Phe⁴,Arg¹⁴,Lys¹⁵]N/OFQ-NH₂ (UFP-102), has been generated by combining in the N/OFQ-NH₂ sequence two chemical modifications, [Arg¹⁴,Lys¹⁵] and [(pF)Phe⁴], that have been previously demonstrated to increase potency. In vitro, UFP-102 bound with high affinity to the human NOP receptor, showed at least 200-fold selectivity over classical opioid receptors, and mimicked N/OFQ effects in CHO_hNOP cells, isolated tissues from various species, and mouse cortical synaptosomes releasing 5-hydroxytryptamine. UFP-102 showed similar maximal effects but higher potency (2- to 48-fold) relative to N/OFQ. The effects of UFP-102 were sensitive to NOP-selective antagonists J-113397 [(±)-trans-1-[1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one] (pA₂ = 7.75–8.12) and UFP-101 ([Nphe¹,Arg¹⁴,Lys¹⁵]N/OFQ-NH₂)(pA₂ = 6.91–7.33) but not to naloxone, and no longer observed in tissues taken from NOP receptor knockout mice (NOP^–/–). In vivo, UFP-102 (0.01–0.3 nmol i.c.v.) mimicked the pronociceptive action of N/OFQ (0.1–10 nmol i.c.v.) in the mouse tail withdrawal assay, displaying higher potency and longer lasting effects. The action of UFP-102 was not apparent in NOP^–/– mice. Similar results were obtained measuring locomotor activity in mice. In conscious rats, UFP-102 (0.05 nmol i.c.v.) produced a marked and sustained decrease in heart rate, mean arterial pressure, and urinary sodium excretion and a profound increase in urine flow rate. These effects were comparable with those evoked by N/OFQ at 5 nmol. Collectively, these findings demonstrate that UFP-102 behaves as a highly potent and selective NOP receptor agonist that produces long-lasting effects in vivo.

Address correspondence to: Dr. Girolamo Calo', Department of Experimental and Clinical Medicine, Section of Pharmacology, via Fossato di Mortara 19, 44100 Ferrara, Italy. E-mail: g.calo{at}unife.it

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