Nociceptin antagonism: probing the receptor by N-acetyl oligopeptides
| Autor: | Anna Magyar, Özge Gündüz, Sándor Benyhe, László Kocsis, Andás Z. Rónai, Brice Bes, Anna Borsodi, Jean Claude Meunier, Erzsébet Kató, Mahmoud Al-Khrasani, Géza Tóth, György Orosz |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Agonist
Physiology Stereochemistry medicine.drug_class Narcotic Antagonists Clinical Biochemistry NOP GTPgammaS CHO Cells Biochemistry Nociceptin Receptor Mice Radioligand Assay Cellular and Molecular Neuroscience chemistry.chemical_compound Endocrinology Cricetinae medicine Animals Receptor Antagonist Ligand (biochemistry) Rats Nociceptin receptor chemistry Competitive antagonist Receptors Opioid Oligopeptides Signal Transduction |
| Zdroj: | Regulatory Peptides. 122:199-207 |
| ISSN: | 0167-0115 |
| DOI: | 10.1016/j.regpep.2004.06.019 |
| Popis: | 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 kappa-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, [(35)S]GTPgammaS 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 (K(e)) of 2.44 nM, and no agonist effect at 10 microM ligand concentration. Schild-analysis indicated a clearly competitive interaction at the NOP receptor, whereas the peptide did not affect the action of the delta-opioid receptor agonist [D-Ala(2),D-Leu(5)]enkephalin. Ac-RYYRIK-ol also exhibited a high affinity in [(3)H]nociceptin-NH(2) binding competition assays using rat brain membranes. Agonist-induced G-protein activation via NOP receptors was studied in [(35)S]GTPgammaS 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. |
| Databáze: | OpenAIRE |
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