Comparative biochemical and pharmacological characterization of a novel,NOP receptor selective hexapeptide,Ac-RYYRIR-ol |
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| Authors: | Engin Bojnik Fruzsina Babos Carmela Fischetti Anna Magyar Valeria Camarda Anna Borsodi Sándor Bajusz Girolamo Calo’ Sándor Benyhe |
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| Affiliation: | 1. Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, 6726 Szeged, Temesvari krt 62, Hungary;2. Research Group of Peptide Chemistry, Hungarian Academy of Sciences and Eötvös Lorand University, P.O. Box 32, 1518 Budapest, 112, Hungary;3. Department of Experimental and Clinical Medicine, Section of Pharmacology, and Neuroscience Center, University of Ferrara, and National Institute of Neuroscience, University of Ferrara, via Fossato di Mortara 17/19, I-44100 Ferrara, Italy;4. Standing Committee for Peptide Chemistry, Hungarian Academy of Sciences, Budapest, Hungary;1. Pharmaceutical Department, University of Parma, Parma, Italy;2. Respiratory Technology, The Woolcock Institute of Medical Research, Glebe 2037, Australia;3. Discipline of Pharmacology, Sydney Medical School, The University of Sydney, NSW 2006, Australia;4. School of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, Australia;1. Grünenthal GmbH, Global Preclinical Drug Development, Department of Pain Pharmacology, Zieglerstrasse 6, 52078 Aachen, Germany;2. Grünenthal GmbH, Global Preclinical Drug Development, Department of Molecular Pharmacology, Aachen, Germany;3. Departments of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri 65212;5. Pathology and Anatomical Sciences, University of Missouri, Columbia, Missouri 65212;4. Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana 46617;6. Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, Indiana 46617;1. Department of Pediatrics, Children’s Hospital of Richmond at Virginia Commonwealth University, Richmond, VA;2. Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA |
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| Abstract: | Nociceptin/orphanin FQ (N/OFQ) is an endogenous neuropeptide, which is widely distributed in central and peripheral nervous system. Some N/OFQ sequence unrelated hexapeptides can effectively bind to the N/OFQ peptide (NOP) receptor and they were used as template for structure-activity studies that lead to discovery of the new NOP selective ligands. In the present study, the pharmacological profile of the novel hexapeptide Ac-RYYRIR-ol was investigated using various in vitro assays including receptor binding and G-protein activation in rat brain membranes, mouse and rat vas deferens, guinea pig ileum, mouse colon and Ca2+ mobilization assay in chinese hamster ovary (CHO) cells co-expressing the human recombinant NOP receptor and the C-terminally modified Gαqi5 protein. In rat brain membranes Ac-RYYRIR-ol displaced both [3H]nociceptin/OFQ and [3H]Ac-RYYRIK-ol with high affinity (pKi 9.35 and 8.81, respectively) and stimulated [35S]GTPγS binding showing however lower maximal effects than N/OFQ (α = 0.28). The stimulatory effect of Ac-RYYRIR-ol was antagonized by the selective NOP receptor antagonist UFP-101. In the electrically stimulated mouse vas deferens Ac-RYYRIR-ol displayed negligible agonist activity while antagonizing in a competitive manner (pA2 7.99) the inhibitory effects of N/OFQ. Similar results were obtained in the rat vas deferens. In the mouse colon Ac-RYYRIR-ol produced concentration dependent contractile effects with similar potency and maximal effects as N/OFQ. Finally, in the Ca2+ mobilization assay performed with CHO-hNOP-Gαqi5 cells Ac-RYYRIR-ol displayed lower potency and maximal effects (α = 0.87) compared with N/OFQ. In conclusion, the novel NOP receptor selective hexapeptide Ac-RYYRIR-ol has been shown to have fine selectivity, high potency, furthermore agonist and antagonist effects toward the NOP receptors were measured in various assays; this is likely due to its partial agonist pharmacological activity. |
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