Synthesis and biological activity of nociceptin/orphanin FQ analogues substituted in position 7 or 11 with Cα,α-dialkylated amino acids

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-NH2 analogues substituted in position 7 and 11 with C alpha,alpha-disubstituted cyclic, linear and branched amino acids. None of the 20 novel N/OFQ analogues produced better results than [Aib(7)]N/OFQ-NH2. 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-NH2 (coded as UFP- 111), compound 22 [(pF)Phe(4) Aib(7) Arg(14) Lys(15)] N/OFQ-NH2 (UFP-112) and compound 23 [Phe psi(CH2-NH)Gly(2) (pF)Phe(4)Aib(7)Arg(14)Lys(15)]N/OFQ-NH2 (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. (c) 2007 Elsevier Ltd. All rights reserved.