title: A novel and facile synthesis of tetra branched derivatives of nociceptin/orphanin FQ.
abstract: Branched peptides have been found to be useful in several research fields however their synthesis and purification is complicated. Here we present a novel and facile synthesis of tetra branched derivatives of nociceptin/orphanin FQ (N/OFQ). Three N/OFQ tetra branched derivatives were prepared using novel cores (PWT1, PWT2 and PWT3) containing a maleimido moiety. [Cys(18)]N/OFQ-NH2 was linked to the cores via thiol-Michael reaction characterized by high yield and purity of the desired final product. In the electrically stimulated mouse vas deferens PWT-N/OFQ derivatives mimicked the inhibitory action of the natural sequence showing similar maximal effects and 3 fold higher potencies. The NOP selective antagonist SB-612111 antagonized the effects of N/OFQ and PWT derivatives with similar pKB values (8.02-8.48). In vivo after supraspinal administration PWT2-N/OFQ stimulated food intake in mice mimicking the action of N/OFQ. Compared to the natural peptide PWT2-N/OFQ was 40 fold more potent and elicited larger effects. These findings suggest that the PWT chemical strategy can be successfully applied to biologically active peptides to generate, with unprecedented high purity and yield, tetra branched derivatives displaying an in vitro pharmacological profile similar to that of the natural sequence associated, in vivo, to increased potency and effectiveness.
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121 Ferrara, Italy; Laboratorio per le tecnologie delle terapie avanzate (LTTA), University of Ferrara, 44121 Ferrara, Italy. Electronic address: r.guerrini@unife.it.
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121 Ferrara, Italy; Laboratorio per le tecnologie delle terapie avanzate (LTTA), University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Marzola
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Trapella
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Pela'
authors.affiliation: Department of Medical Science, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Molinari
authors.affiliation: Department of Medical Science, 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 Medical Science, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Malfacini
authors.affiliation: Department of Medical Science, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Rizzi
authors.affiliation: Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121 Ferrara, Italy; Laboratorio per le tecnologie delle terapie avanzate (LTTA), University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Severo
authors.initials: S
authors.lastname: Salvadori
authors.affiliation: Department of Medical Science, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy.
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calo'
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects*; D004558:Electric Stimulation; D007276:Injections, Intraventricular; D008024:Ligands; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D018847:Opioid Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000819:agonists*; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D008024:Ligands; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C000722287:Oprl1 protein, mouse
keywords: Branched peptide; In vivo activity; Nociceptin/orphanin FQ