title: N- and C-terminal modifications of nociceptin/orphanin FQ generate highly potent NOP receptor ligands.
abstract: Previous structure-activity studies on nociceptin/orphanin FQ (N/OFQ) identified [Phe(1)Psi(CH(2)NH)Gly(2)]N/OFQ(1-13)-NH(2) and [Nphe(1)]N/OFQ(1-13)-NH(2) as a N/OFQ peptide receptor (NOP) partial agonist and pure antagonist, respectively. The addition of fluorine to the Phe(4) or the insertion of a further pair of basic amino acids Arg(14)-Lys(15) generate potent agonists. On the basis of these findings, we combined in the N/OFQ-NH(2) template the chemical modifications Arg(14)-Lys(15) and (pF)Phe(4) that increase the agonist potency with those conferring partial agonist (Phe(1)Psi(CH(2)NH)Gly(2)) or pure antagonist (Nphe(1)) properties. Twelve peptides were synthesized and pharmacologically evaluated in Chinese hamster ovary cells expressing the human recombinant NOP and in electrically stimulated mouse vas deferens and guinea pig ileum assays. All peptides behaved as NOP ligands; the chemical modifications Arg(14)-Lys(15) and (pF)Phe(4) increased ligand affinity/potency. Peptides with the normal Phe(1)-Gly(2) peptide bond behaved as full agonists, and those with the Phe(1)Psi(CH(2)NH)Gly(2) modification behaved as partial agonists, while those with the Nphe(1) modification behaved as partial agonists or pure antagonists depending on the presence or absence of the (pF)Phe(4) modification, respectively. The full agonist [(pF)Phe(4),Arg(14),Lys(15)]N/OFQ-NH(2), the partial agonist [Phe(1)Psi(CH(2)NH)Gly(2),(pF)Phe(4),Arg(14),Lys(15)]N/OFQ-NH(2), and the pure antagonist [Nphe(1),Arg(14),Lys(15)]N/OFQ-NH(2) represent the most potent peptide ligands for NOP.
authors.affiliation: Department of Pharmaceutical Sciences and Biotechnology Center and Department of Experimental and Clinical Medicine, Section of Pharmacology and Neuroscience Centre, University of Ferrara, 44100 Ferrara, Italy.
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Girolamo
authors.initials: G
authors.lastname: Caló
authors.forename: David G
authors.initials: DG
authors.lastname: Lambert
authors.forename: Giacomo
authors.initials: G
authors.lastname: Carrá
authors.forename: Marika
authors.initials: M
authors.lastname: Arduin
authors.forename: Tim A
authors.initials: TA
authors.lastname: Barnes
authors.forename: John
authors.initials: J
authors.lastname: McDonald
authors.forename: Daniela
authors.initials: D
authors.lastname: Rizzi
authors.forename: Claudio
authors.initials: C
authors.lastname: Trapella
authors.forename: Erika
authors.initials: E
authors.lastname: Marzola
authors.forename: David J
authors.initials: DJ
authors.lastname: Rowbotham
authors.forename: Domenico
authors.initials: D
authors.lastname: Regoli
authors.forename: Severo
authors.initials: S
authors.lastname: Salvadori
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004558:Electric Stimulation; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000502:physiology; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D009292:Narcotic Antagonists; D018847:Opioid Peptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D011957:Receptors, Opioid / Q000819:agonists*; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000502:physiology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D008024:Ligands; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D011957:Receptors, Opioid; D011994:Recombinant Proteins; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C479838:(Nphe(1),Arg(14),Lys(15))N-OFQ NH(2); C498512:UFP-102; C499140:nociceptin-orphanin FQ-amide, phenylalanyl(1)-psi(CH2NH)-glycyl(2)-4-fluorophenylalanyl(4)-arginyl(14)-lysyl(15)-