Evidence that [Phe1ψ(CH2‐NH)Gly2]nociceptin‐(1‐13)‐NH2, a peripheral ORL‐1 receptor antagonist, acts as an agonist in the rat spinal cord

Carpenter, Kate J.; Dickenson, Anthony H.

doi:10.1038/sj.bjp.0702188

Cited by 52 publications

(20 citation statements)

References 11 publications

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“…In several isolated tissues 18,[29][30][31][32] and in the cardiovascular system of the mouse in vivo, compound 2b behaves as an antagonist, while this pseudopeptide is a potent agonist in several tests on central actions of NC. 11,12,[34][35][36][37] The full agonist activity of compound 2b in CHO NCR cells has been confirmed in different laboratories (present data and 33,45,46 ). The reasons for the dual behavior of compound 2b are at present unknown; however, recent findings suggest that the intrinsic activity of the compound may depend on the number of NC receptors expressed in a given preparation 47 (see ref 38 for a detailed discussion of this topic).…”

Section: Resultssupporting

confidence: 80%

Further Studies on Nociceptin-Related Peptides: Discovery of a New Chemical Template with Antagonist Activity on the Nociceptin Receptor

et al. 2000

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Three series of nociceptin (NC)-related peptides were synthesized and their abilities (i) to bind to the NC sites expressed in mouse forebrain membranes, (ii) to inhibit the electrically evoked contraction of the mouse vas deferens, and (iii) to inhibit forskolin-stimulated cAMP accumulation in Chinese hamster ovary cells expressing the human recombinant NC receptor (CHONCR) were investigated. The compounds of the first series (a series) have an ordinary Xaa1-Gly2 bond, those of the second series (b series) have a Xaa1psi(CH2-NH)Gly2 pseudopeptide bond, and those of the third series (c series) have a peptoid (Nxaa1-Gly2) structure. The affinity values measured in the binding assay and in the two functional assays with the compounds of the three series showed high levels of correlation. Thus, (I) the compounds of the a series in which Phe1 was substituted with Tyr, Cha, or Leu acted as potent NC receptor agonists; (II) the b series compounds behaved as NC receptor antagonists in the mouse vas deferens and as full agonists in CHO(NCR) cells with different potencies depending on the first amino acid residue, [Phe1psi(CH2-NH)Gly2]NC(1-17)NH2 and [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 being the most potent compounds; (III) the compounds of the third series were all inactive both as agonists and as antagonists with the exception of [Nphe1]NC(1-17)NH2 and [Nphe1]NC(1-13)NH2, which behaved as NC receptor antagonists both in the isolated tissue and in CHO(NCR) cells (pKB 6.1-6.4). In conclusion, this study demonstrates that chemical requirements for NC receptor agonists are different from those of antagonists. Moreover, modifications of the steric orientation of the aromatic residue Phe1 in the NC sequence as obtained with the pseudopeptide bond between Phe1 and Gly2 or with the displacement of the benzyl side chain by one atom, as in Nphe1, lead respectively to reduction or elimination of efficacy. Indeed, in contrast to [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 which has been reported to exhibit agonist activity in several assays involving either central or recombinant NC receptors, [Nphe1]NC(1-13)NH2 antagonizes the effect of NC at human recombinant NC receptors and in the mouse tail withdrawal assay.

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Section: Resultssupporting

confidence: 80%

Further Studies on Nociceptin-Related Peptides: Discovery of a New Chemical Template with Antagonist Activity on the Nociceptin Receptor

et al. 2000

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“…This report set off a flurry of in vitro and in vivo assays (nicely summarized in Calo et al, 2000b) which showed, to some disappointment, that this peptide acted as an antagonist, partial agonist, or even full agonist, depending on the tissue preparation. Thus, while it showed different levels of partial agonist activity in [ 35 S]GTPγS assays in CHO cells transfected with human or mouse ORL1 (Burnside et al, 2000;Berger et al, 2000), it showed full agonist activity in several in vivo CNS assays (Xu et al, 1998;Grisel et al, 1998;Carpenter and Dickenson, 1998). Similar results were also observed with the partial agonist hexapeptide Ac-RYYRIK-NH 2 (Berger et al, 2000;Burnside et al, 2000).…”

Section: Peptide Ligandssupporting

confidence: 71%

Peptide and nonpeptide ligands for the nociceptin/orphanin FQ receptor ORL1: Research tools and potential therapeutic agents

Zaveri

2003

Life Sciences

109

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The 17-amino acid neuropeptide nociceptin/Orphanin FQ (N/OFQ) was recently identified as the endogenous ligand for the opioid receptor-like (ORL1) receptor, a fourth member of the classical μ, δ, and κ opioid receptor family. Although ORL1 clearly belongs to the opioid receptor family, it does not bind classical opiates and the ORL1-N/OFQ system has pharmacological actions distinct from the opioid receptor system. This new ligand-receptor system has generated active interest in the opioid community because of its wide distribution and involvement in a myriad of neurological pathways. The past two years have witnessed tremendous advances in the design and discovery of very potent and selective peptide and nonpeptide agonist and antagonist ligands at ORL1. These discoveries have facilitated the understanding of the role of the ORL1-N/OFQ system in a variety of processes such as pain modulation, anxiety, food intake, learning, memory, neurotransmitter release, reward pathways, and tolerance development. The ORL1 receptor therefore represents a new molecular target for the design of novel agents for anxiety, analgesia, and drug addiction. Indeed, there is tremendous interest in the pharmaceutical industry in the development of nonpeptide ligands such as the potent ORL1 agonist, Ro 64-6198, as anxiolytics and the ORL1 antagonist JTC-801 as novel analgesics. This review presents an overview of the various peptide and nonpeptide ORL1 ligands with an emphasis on their potential therapeutic utility in various human disorders.

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“…These findings suggest that [F/G]NC(1-13)NH 2 interacts with central NC receptors controlling food intake and acts as a full agonist. Such a suggestion emerges also from a series of recent reports in which [F/G]NC(1-13)NH 2 has been found to mimic the actions of NC in the rat spinal cord (Candeletti et al 1998;Carpenter and Dickenson 1998;Xu et al 1998), in the mouse brain (Calo' et al 1998a;Grisel et al 1998) or in cells expressing the human ORL1 receptor (Butour et al 1998;Okawa et al 1999). In addition, [F/G]NC(1-13)NH 2 has been demonstrated to act as a partial agonist on NC sites that inhibit noradrenaline release from mouse cerebral cortex slices (Schlicker et al 1998) and in cell cultures expressing low levels of NC receptors (Olianas et al 1999).…”

Section: Discussionmentioning

confidence: 69%

Pharmacological characterization of the nociceptin receptor mediating hyperphagia: identification of a selective antagonist

et al. 2000

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Evidence that [Phe¹ψ(CH₂‐NH)Gly²]nociceptin‐(1‐13)‐NH₂, a peripheral ORL‐1 receptor antagonist, acts as an agonist in the rat spinal cord

Cited by 52 publications

References 11 publications

Further Studies on Nociceptin-Related Peptides: Discovery of a New Chemical Template with Antagonist Activity on the Nociceptin Receptor

Further Studies on Nociceptin-Related Peptides: Discovery of a New Chemical Template with Antagonist Activity on the Nociceptin Receptor

Peptide and nonpeptide ligands for the nociceptin/orphanin FQ receptor ORL1: Research tools and potential therapeutic agents

Pharmacological characterization of the nociceptin receptor mediating hyperphagia: identification of a selective antagonist

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