title: Synthesis and biological activity of nociceptin/orphanin FQ analogues substituted in position 7 or 11 with Calpha,alpha-dialkylated amino acids.
abstract: Previous structure-activity and NMR studies on nociceptin/orphanin FQ (N/OFQ) demonstrated that Aib substitution of Ala(7) and/or Ala(11) increases the peptide potency through an alpha helix structure induction mechanism. On these bases we synthesised and evaluated pharmacologically in the mouse vas deferens assay a series of N/OFQ-NH(2) analogues substituted in position 7 and 11 with Calpha,alpha-disubstituted cyclic, linear and branched amino acids. None of the 20 novel N/OFQ analogues produced better results than [Aib(7)]N/OFQ-NH(2). Thus, this substitution was combined with other chemical modifications known to modulate peptide potency and/or efficacy generating compound 21 [Nphe(1)Aib(7)Arg(14)Lys(15)]N/OFQ-NH(2) (coded as UFP-111), compound 22 [(pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ-NH(2) (UFP-112) and compound 23 [Phe(1)Psi(CH(2)-NH)Gly(2)(pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ-NH(2) (UFP-113). These novel peptides behaved as highly potent NOP receptor ligands showing full (UFP-112) and partial (UFP-113) agonist and pure antagonist (UFP-111) activities in a series of in vitro functional assays performed on pharmacological preparations expressing native as well as recombinant NOP receptors.
authors.affiliation: Department of Pharmaceutical Sciences and Biotechnology Center, University of Ferrara, 44100 Ferrara, Italy.
authors.forename: Marika
authors.initials: M
authors.lastname: Arduin
authors.forename: Barbara
authors.initials: B
authors.lastname: Spagnolo
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calò
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Giacomo
authors.initials: G
authors.lastname: Carrà
authors.forename: Carmela
authors.initials: C
authors.lastname: Fischetti
authors.forename: Claudio
authors.initials: C
authors.lastname: Trapella
authors.forename: Erika
authors.initials: E
authors.lastname: Marzola
authors.forename: John
authors.initials: J
authors.lastname: McDonald
authors.forename: David G
authors.initials: DG
authors.lastname: Lambert
authors.forename: Domenico
authors.initials: D
authors.lastname: Regoli
authors.forename: Severo
authors.initials: S
authors.lastname: Salvadori
mesh_terms: D000215:Acylation; D000478:Alkylation; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004558:Electric Stimulation; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D009130:Muscle, Smooth / Q000187:drug effects; D018847:Opioid Peptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012015:Reference Standards; D014649:Vas Deferens / Q000187:drug effects; D000097629:Nociceptin
chemical_list: D000596:Amino Acids; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D008024:Ligands; D018847:Opioid Peptides; D000097629:Nociceptin