title: In vitro and in vivo studies on UFP-112, a novel potent and long lasting agonist selective for the nociceptin/orphanin FQ receptor.
abstract: [(pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ-NH(2) (UFP-112) has been designed as a novel ligand for the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) by combining into the same peptide different chemical modifications reported to increase N/OFQ potency. In vitro data obtained in the electrically stimulated mouse vas deferens demonstrated that UFP-112 behaved as a high potency (pEC(50) 9.43) full agonist at the NOP receptor. UFP-112 effects were sensitive to the NOP antagonist UFP-101 but not to naloxone and no longer evident in tissues taken from NOP(-/-) mice. In vitro half life of UFP-112 in mouse plasma and brain homogenate was 2.6- and 3.5-fold higher than that of N/OFQ. In vivo, in the mouse tail withdrawal assay, UFP-112 (1-100pmol, i.c.v.) mimicked the actions of N/OFQ producing pronociceptive effects after i.c.v. administration and antinociceptive effects when given i.t.; in both cases, UFP-112 was approximately 100-fold more potent than the natural peptide and produced longer lasting effects. UFP-112 also mimicked the hyperphagic effect of N/OFQ producing a bell shaped dose response curve with the maximum reached at 10pmol. The hyperphagic effects of N/OFQ and UFP-112 were absent in NOP(-/-) mice. Equi-effective high doses of UFP-112 (0.1nmol) and N/OFQ (10nmol) were injected i.c.v. in mice and spontaneous locomotor activity recorded for 16h. N/OFQ produced a clear inhibitory effect which lasted for 60min while UFP-112 elicited longer lasting effects (>6h). In conscious rats, UFP-112 (0.1 and 10nmol/kg, i.v.) produced a marked and sustained decrease in heart rate, blood pressure, and urinary sodium excretion and a profound increase in urine flow. Collectively, these findings demonstrate that UFP-112 behaves in vitro and in vivo as a highly potent and selective ligand able to produce full and long lasting activation of NOP receptors.
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, Via Fossato di Mortara 17, 44100 Ferrara, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Rizzi
authors.forename: Barbara
authors.initials: B
authors.lastname: Spagnolo
authors.forename: Richard D
authors.initials: RD
authors.lastname: Wainford
authors.forename: Carmela
authors.initials: C
authors.lastname: Fischetti
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Giuliano
authors.initials: G
authors.lastname: Marzola
authors.forename: Anna
authors.initials: A
authors.lastname: Baldisserotto
authors.forename: Severo
authors.initials: S
authors.lastname: Salvadori
authors.forename: Domenico
authors.initials: D
authors.lastname: Regoli
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Kapusta
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calo
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004558:Electric Stimulation; D004594:Electrophysiology; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects; D018847:Opioid Peptides / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists* / Q000187:drug effects; D012964:Sodium / Q000652:urine; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology; D000094942:Nociceptin Receptor
chemical_list: C479838:(Nphe(1),Arg(14),Lys(15))N-OFQ NH(2); D018847:Opioid Peptides; D011957:Receptors, Opioid; D012964:Sodium; D000094942:Nociceptin Receptor