Nociceptin antagonism: Probing the receptor by N-acetyl oligopeptides

László Kocsis, György Orosz, Anna Magyar, Mahmoud Al-Khrasani, Erzsébet Kató, Andás Z. Rónai, Brice Bes, Jean Claude Meunier, Özge Gündüz, Géza Tóth, Anna Borsodi, Sándor Benyhe

Research output: Contribution to journalArticle

18 Citations (Scopus)


In search for effective antagonist structures for the nociceptin (NOP) receptor, a number of N-acylated oligopeptides, including N-acyl tetra- and pentapeptides selective for the κ-opioid receptor, as well as N-acyl hexapeptides bearing the Ac-Arg-Tyr-Tyr-Arg-Ile-Lys (Ac-RYYRIK) core sequence originally isolated from combinatorial chemical libraries, were synthesized and studied in radioreceptor binding assays, [35S]GTPγS functional tests and in mouse vas deferens (MVD) bioassays. The properties of the novel antagonist candidates were compared to known antagonists. A new antagonist structure with a reduced, primer alcohol C-terminus, Ac-Arg-Tyr-Tyr-Arg-Ile- lysinol (Ac-RYYRIK-ol) was described in the mouse vas deferens tests, showing an equilibrium inhibitory constant value (Ke) of 2.44 nM, and no agonist effect at 10 μM ligand concentration. Schild-analysis indicated a clearly competitive interaction at the NOP receptor, whereas the peptide did not affect the action of the δ-opioid receptor agonist [D-Ala 2,D-Leu5]enkephalin. Ac-RYYRIK-ol also exhibited a high affinity in [3H]nociceptin-NH2 binding competition assays using rat brain membranes. Agonist-induced G-protein activation via NOP receptors was studied in [35S]GTPγS binding stimulation assays by the use of both native brain tissue preparations and membranes from cultured CHO cells expressing recombinant nociceptin receptors. Ac-RYYRIK-ol displayed only weak intrinsic agonist activity, whereas it effectively inhibited the stimulation generated by nociceptin. The results support the high potency and antagonist nature of Ac-RYYRIK-ol and reveal important roles for both the N- and the C-terminal region of the molecule.

Original languageEnglish
Pages (from-to)199-207
Number of pages9
JournalRegulatory Peptides
Issue number3
Publication statusPublished - Nov 15 2004


  • GTPγS assay
  • Mouse vas deferens bioassay
  • NOP receptor
  • Nociceptin
  • Peptide antagonist
  • Radioligand binding

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Endocrinology
  • Clinical Biochemistry
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Nociceptin antagonism: Probing the receptor by N-acetyl oligopeptides'. Together they form a unique fingerprint.

  • Cite this