@article {Carr{\`a}1114, author = {Giacomo Carr{\`a} and Anna Rizzi and Remo Guerrini and Timothy A. Barnes and John McDonald and Christopher P. Hebbes and Flora Mela and Velga A. Kenigs and Giuliano Marzola and Daniela Rizzi and Elaine Gavioli and Silvia Zucchini and Domenico Regoli and Michele Morari and Severo Salvadori and David J. Rowbotham and David G. Lambert and Daniel R. Kapusta and Girolamo Calo{\textquoteright}}, title = {[(pF)Phe4,Arg14,Lys15]N/OFQ-NH2 (UFP-102), a Highly Potent and Selective Agonist of the Nociceptin/Orphanin FQ Receptor}, volume = {312}, number = {3}, pages = {1114--1123}, year = {2005}, doi = {10.1124/jpet.104.077339}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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 CHOhNOP 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 [({\textpm})-trans-1-[1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one] (pA2 = 7.75{\textendash}8.12) and UFP-101 ([Nphe1,Arg14,Lys15]N/OFQ-NH2)(pA2 = 6.91{\textendash}7.33) but not to naloxone, and no longer observed in tissues taken from NOP receptor knockout mice (NOP{\textendash}/{\textendash}). In vivo, UFP-102 (0.01{\textendash}0.3 nmol i.c.v.) mimicked the pronociceptive action of N/OFQ (0.1{\textendash}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{\textendash}/{\textendash} 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. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/312/3/1114}, eprint = {https://jpet.aspetjournals.org/content/312/3/1114.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }