Characterization of Nociceptin/Orphanin FQ-Induced Pain Responses by the Novel Receptor Antagonist<i>N-</i>(4-Amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) Benzamide Monohydrochloride

Muratani, Tadatoshi; Minami, Toshiaki; Enomoto, Utako; Sakai, Masato; Okuda‐Ashitaka, Emiko; Kiyokane, Kimihiro; Mori, Hidemaro; Ito, Seiji

doi:10.1124/jpet.102.036095

Cited by 25 publications

(23 citation statements)

References 28 publications

(41 reference statements)

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“…To address this question, both NOP receptor antagonists (summarized in Table 1) and mice lacking either the NOP receptor or the N/OFQ precursor protein ppN/OFQ ( (Calò et al, 2000a. These results are in excellent agreement with the previous (Shinkai et al, 2000;Muratani et al, 2002;Yamada et al, 2002). At present, it is not entirely clear whether this apparent antinociceptive effect is indeed mediated via an antagonism at NOP receptors.…”

Section: Synthetic Nop Receptor Antagonistssupporting

confidence: 82%

Nociceptin/Orphanin FQ and Its Receptor—Potential Targets for Pain Therapy?

Zeilhofer¹,

Calò²

2003

J Pharmacol Exp Ther

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The neuropeptide nociceptin, also called orphanin FQ (N/OFQ), is the endogenous agonist of the N/OFQ peptide receptor (NOP receptor). Both N/OFQ and the NOP receptor share a high degree of homology with classical opioid peptides and opioid receptors, respectively, and use similar signal transduction pathways as classical opioids. The NOP receptor has thus been regarded as the fourth member of the opioid receptor family. Despite this close relationship, 7 years of research have demonstrated that the N/OFQ system has a distinct pharmacological profile and serves different physiological functions. In particular, its role in the control of pain and analgesia at different levels of integration appears quite different from that of classical opioids. The recent development of specific antagonists at the NOP receptor and of NOP receptor or N/OFQ precursor knock-out mice have generated new insights into the role of N/OFQ in pain processing and help to evaluate the N/OFQ-NOP system as a potential target for new analgesic drugs.While acute-particularly post-traumatic and postsurgical pain can be treated satisfactorily with available analgesics in most cases-chronic inflammatory and neuropathic pain often responds only poorly. The identification of novel targets for analgesic therapy is therefore a major focus in current pharmacological research. Chronic pain states are frequently accompanied by an increased pain sensitivity, which can appear as hyperalgesia, an increased sensitivity to noxious stimuli, or allodynia, a painful sensation of usually innocuous stimuli. N/OFQ has repeatedly been implicated in the development and/or modulation of both phenomena and has thus attracted significant attention in current pain research.The discovery of N/OFQ is a prominent example of so called reverse pharmacology in which a receptor was known before the corresponding ligand could be identified (Civelli et al., 1998). Soon after the discovery of the ␦ opioid (DOP) receptor by expression cloning molecular biologists have not only identified the expected and (MOP and KOP) opioid receptors, but also a fourth unperceived receptor, which does not bind classical opioids. The human homolog of this receptor has therefore been termed opioid receptor-like 1 receptor (Mollereau et al., 1994). Only 1 year after its discovery, a 17 amino acid neuropeptide was identified as the endogenous agonist by two independent groups and called nociceptin (Meunier et al., 1995) or orphanin FQ (Reinscheid et al., 1995). Both the peptide and its receptor, now called N/OFQ peptide (NOP) receptor, share a high degree of homology with classical opioid peptides (namely dynorphin A) and classical opioid receptors (namely the opioid peptide receptor). A first series of behavioral tests has suggested that this peptide was pro-rather than antinociceptive, when injected intracerebroventricularly (i.c.v.). This effect led Meunier et al. (1995) to coin the term nociceptin. Reinscheid et al. (1995) called the peptide orphanin FQ, indicating that the peptide activat...

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Section: Synthetic Nop Receptor Antagonistssupporting

confidence: 82%

Nociceptin/Orphanin FQ and Its Receptor—Potential Targets for Pain Therapy?

Zeilhofer¹,

Calò²

2003

J Pharmacol Exp Ther

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“…However, these data contrast with previous work by Yamamoto et al (1997), showing that intrathecal injection of nociceptin reduces allodynia and thermal hyperalgesia induced by carrageenan injection into the rat paw. These discrepancies may be explained by the dose dependence of pro-versus antinociceptive activities of nociceptin, as recently described by Muratani et al (2002) using the mouse formalin model of acute pain response. Our data showing that SB-612111 can reverse carrageenan-induced hyperalgesia are consistent with a role of nociceptin in the negative regulation of excitatory neurotransmission.…”

Section: Discussionmentioning

confidence: 99%

“…After systemic administration, JTC-801 blocks the allodynic effect of nociceptin and is active per se in the mouse hot-plate and rat formalin tests, both models of an acute pain response. Muratani et al (2002) further showed that JTC-801 can block pronociceptive effects caused by low doses of nociceptin in the formalin test but is unable to alter its antinociceptive effects at high doses. The benzimidizole analog J-113397 has been reported by Ozaki et al (2000) as having high affinity and selectivity for the ORL-1 receptor (K i ϭ 1.8 nM), antagonist activity in a test of nociceptin-stimulated […”

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confidence: 99%

Modification of Nociception and Morphine Tolerance by the Selective Opiate Receptor-Like Orphan Receptor Antagonist (–)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111)

Zaratin

Petrone²,

Sbacchi³

et al. 2003

J Pharmacol Exp Ther

138

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ABSTRACT(Ϫ)-cis-1- piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111) is a novel human opiate receptor-like orphan receptor (ORL-1) antagonist that has high affinity for the clonal human ORL-1 receptor (hORL-1 K i ϭ 0.33 nM), selectivity versus -(174-fold), ␦-(6391-fold), and (486-fold)-opioid receptors and is able to inhibit nociceptin signaling via hORL-1 in a whole cell gene reporter assay. SB-612111 has no measurable antinociceptive effects in vivo in the mouse hot-plate test after intravenous administration but is able to antagonize the antimorphine action of nociceptin [ED 50 ϭ 0.69 mg/kg, 95% confidence limit (CL) ϭ 0.34 -1.21]. SB-62111 administration can also reverse tolerance to morphine in this model, established via repeated morphine administration. In addition, intravenous SB-612111 can antagonize nociceptin-induced thermal hyperalgesia in a dose-dependent manner (ED 50 ϭ 0.62 mg/kg i.v., 95% CL ϭ 0.22-1.89) and is effective per se at reversing thermal hyperalgesia in the rat carrageenan inflammatory pain model. These data show that an ORL-1 receptor antagonist may be a useful adjunct to chronic pain therapy with opioids and can be used to treat conditions in which thermal hyperalgesia is a significant component of the pain response.Nociceptin (orphanin FQ) is a 17-amino acid peptide identified as a potent endogenous agonist for the opiate receptorlike orphan receptor (ORL-1), a G protein-coupled receptor with a high degree of structural homology to the classical opioid receptors (Mollereau et al., 1994). Despite the high similarity in sequence between nociceptin and other opioid peptides, notably dynorphin A, nociceptin does not interact with -, ␦-, or -opioid receptors, and opioid peptides do not interact with the ORL-1 receptor (Meunier et al., 1995). Activation of the ORL-1 receptor with nociceptin can enhance cellular K ϩ conductance (Vaughan et al., 1997), inhibit Ca 2ϩ currents associated with N, L, and P/Q calcium channel activation (Knoflach et al., 1996;Connor and Christie, 1998), and block cellular cAMP production (Butour et al., 1997). These signaling mechanisms are represented in areas of the nervous system that are crucial for pain transmission, and nociceptin can act via these pathways to influence, for example, glutamate and GABA release in the periaqueductal gray (Vaughan et al., 1997) and neuronal activity in the dorsal root of the spinal cord (Lai et al., 1997). Furthermore, peptide antagonists of the ORL-1 receptor such as [N-Phe 1 ]nociceptin(1-13)NH 2 and UFP-101 have been shown to inhibit presynaptic 5-hydroxytryptaArticle, publication date, and citation information can be found at

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“…[22][23][24] The fl at planar structure of JTC-801 is clearly distinct from that of almost all reported NOP ligands. It is likely that JTC-801 binds to the NOP receptor at a site partially overlapping the active site where most piperidinebased ligands anchor, via the electrostatic interaction of the protonated basic nitrogen of the ligand, and the Asp-130 at the active site.…”

Section: E348mentioning

confidence: 85%

Small-Molecule Agonists and Antagonists of the Opioid Receptor-Like Receptor (ORL1, NOP): Ligand-Based Analysis of Structural Factors Influencing Intrinsic Activity at NOP

Zaveri¹,

Jiang²,

Olsen³

et al. 2008

Drug Addiction

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A BSTRACTThe recently discovered fourth member of the opioid receptor family, the nociceptin receptor (NOP) and its endogenous ligand, the heptadecapeptide nociceptin, are involved in several central nervous system pathways, such as nociception, reward, tolerance, and feeding. The discovery of smallmolecule ligands for NOP is being actively pursued for several therapeutic applications. This review presents a brief overview of the several recently reported NOP ligands, classifi ed as NOP agonists and antagonists, with an emphasis on the analysis of the structural features that may be important for modulating the agonist/antagonist profi le (intrinsic activity) of these ligands. Structure-activity relationships in our own series of dihydroindolinone-based NOP ligands and those of the various reported ligands indicate that the li pophilic substituent on the common basic nitrogen present in all NOP ligands plays a role in determining the agonist/antagonist profi le of the NOP ligand. This analysis provides a basis for the rational drug design of NOP ligands of desired intrinsic activity and provides a framework for developing pharmacophore models for high affi nity binding and intrinsic activity at the NOP receptor. Since NOP agonists and antagonists both have therapeutic value, rational approaches for obtaining both within a high-affi nity binding class of compounds are very useful for designing potent and selective NOP ligands with the desired profi le of intrinsic effi cacy.

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Characterization of Nociceptin/Orphanin FQ-Induced Pain Responses by the Novel Receptor AntagonistN-(4-Amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) Benzamide Monohydrochloride

Cited by 25 publications

References 28 publications

Nociceptin/Orphanin FQ and Its Receptor—Potential Targets for Pain Therapy?

Nociceptin/Orphanin FQ and Its Receptor—Potential Targets for Pain Therapy?

Modification of Nociception and Morphine Tolerance by the Selective Opiate Receptor-Like Orphan Receptor Antagonist (–)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111)

Small-Molecule Agonists and Antagonists of the Opioid Receptor-Like Receptor (ORL1, NOP): Ligand-Based Analysis of Structural Factors Influencing Intrinsic Activity at NOP

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