title: Structure- and conformation-activity studies of nociceptin/orphanin FQ receptor dimeric ligands.
abstract: The peptide nociceptin/orphanin FQ (N/OFQ) and the N/OFQ receptor (NOP) constitute a neuropeptidergic system that modulates various biological functions and is currently targeted for the generation of innovative drugs. In the present study dimeric NOP receptor ligands with spacers of different lengths were generated using both peptide and non-peptide pharmacophores. The novel compounds (12 peptide and 7 nonpeptide ligands) were pharmacologically investigated in a calcium mobilization assay and in the mouse vas deferens bioassay. Both structure- and conformation-activity studies were performed. Results demonstrated that dimerization did not modify the pharmacological activity of both peptide and non-peptide pharmacophores. Moreover, when dimeric compounds were obtained with low potency peptide pharmacophores, dimerization recovered ligand potency. This effect depends on the doubling of the C-terminal address sequence rather than the presence of an additional N-terminal message sequence or modifications of peptide conformation.
authors.affiliation: Department of Chemical and Pharmaceutical Sciences and LTTA, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Pacifico
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Carotenuto
authors.affiliation: Department of Agraria (QuaSic.A.Tec.), Università Mediterranea di Reggio Calabria, 89122 - Reggio Calabria, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Brancaccio
authors.affiliation: Department of Pharmacy, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Department of Chemical and Pharmaceutical Sciences and LTTA, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Marzola
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Ferrari
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Maria Camilla
authors.initials: MC
authors.lastname: Cerlesi
authors.affiliation: Department of Chemical and Pharmaceutical Sciences and LTTA, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Trapella
authors.affiliation: Department of Chemical and Pharmaceutical Sciences and LTTA, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Delia
authors.initials: D
authors.lastname: Preti
authors.affiliation: Department of Chemical and Pharmaceutical Sciences and LTTA, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Severo
authors.initials: S
authors.lastname: Salvadori
authors.affiliation: Department of Medical Sciences, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calò
authors.affiliation: Department of Chemical and Pharmaceutical Sciences and LTTA, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000032:analysis; D003412:Cricetulus; D019281:Dimerization; D008024:Ligands; D018847:Opioid Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D055503:Protein Multimerization; D011957:Receptors, Opioid / Q000378:metabolism*; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D002118:Calcium; D008024:Ligands; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin