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

Bioorg Med Chem. 2007 Jul 1;15(13):4434-43. doi: 10.1016/j.bmc.2007.04.026. Epub 2007 Apr 24.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acylation
  • Alkylation
  • Amino Acids / chemistry
  • Animals
  • Binding, Competitive / drug effects
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Electric Stimulation
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • In Vitro Techniques
  • Ligands
  • Male
  • Mice
  • Muscle, Smooth / drug effects
  • Opioid Peptides / chemical synthesis*
  • Opioid Peptides / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Reference Standards
  • Vas Deferens / drug effects

Substances

  • Amino Acids
  • Ligands
  • Opioid Peptides
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • nociceptin