Synthesis and biological activity of nociceptin/orphanin FQ analogues substituted in position 7 or 11 with Cα,α-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 Cα,α-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 1Aib 7Arg 14Lys 15]N/OFQ-NH 2 (coded as UFP-111), compound 22 [(pF)Phe 4Aib 7Arg 14Lys 15]N/OFQ-NH 2 (UFP-112) and compound 23 [Phe 1Ψ(CH 2–NH)Gly 2(pF)Phe 4Aib 7Arg 14Lys 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.