4-Aminoquinolines:  Novel Nociceptin Antagonists with Analgesic Activity

Shinkai, Hisashi; Itō, Takao; Iida, Tetsuya; Kitao, Yuki; Yamada, Hideki; Uchida, Isamu

doi:10.1021/jm0002073

Cited by 144 publications

(89 citation statements)

References 23 publications

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“…SB-612111 is a member of a novel class of nonpeptide antagonists that is structurally unrelated to other nonpeptide ORL-1 receptor ligands that have been described, such as J-113397 (Kawamoto et al, 1999) and JTC-801 (Shinkai et al, 2000).…”

Section: Discussionmentioning

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

142

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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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Section: Discussionmentioning

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

142

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“…On the other hand, the supraspinal administration of antisense oligodeoxynucleotide or antagonist for N/OFQ receptor (NOP) caused an increase in nociceptive threshold (Meunier et al, 1995;Rossi et al, 1997;Zhu et al, 1997;Calo et al, 2000Calo et al, , 2002Shinkai et al, 2000), whereas NOP Ϫ/Ϫ mice displayed normal baseline nociceptive responses in some analgesic paradigms (Nishi et al, 1997;Mamiya et al, 1998;Ozaki et al, 2000). These findings suggest that N/OFQ might play differential pain modulatory roles.…”

Section: In Nopmentioning

confidence: 99%

In Vivo Pain-Inhibitory Role of Nociceptin/Orphanin FQ in Spinal Cord

Inoue¹,

Kawashima²,

Takeshima³

et al. 2003

J Pharmacol Exp Ther

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Because nociceptin/orphanin FQ (N/OFQ) has both pronociceptive (hyperalgesia) and antinociceptive actions in pharmacological experiments, and there is no significant difference in the nociceptive responses between NOP Ϫ/Ϫ mice and their wild-type (NOP ϩ/ϩ ) littermates, the physiological role of N/OFQ in pain regulation remains to be determined. Under the hypothesis that the use of molecularly distinct nociception test may reveal the pain modality-specific role of N/OFQ, we attempted to examine the physiological role of N/OFQ in pain transmission by using newly developed algogenic-induced nociceptive flexion test in NOP Ϫ/Ϫ and NOP ϩ/ϩ mice or NOP antagonisttreated mice. The nociceptive flexor responses upon intraplantar injection of bradykinin or substance P, which stimulates polymodal substance P-ergic fibers, were markedly potentiated in NOP Ϫ/Ϫ mice, compared with those in its NOP ϩ/ϩ mice. However, there were no significant changes in NOP Ϫ/Ϫ mice with adenosine triphosphate or prostaglandin I 2 agonist, which stimulates glutamatergic but not substance P-ergic fibers. The nocifensive responses induced by substance P (i.t.) were also potentiated in NOP Ϫ/Ϫ mice. On the other hand, there were no significant differences in NK1-like immunoreactivity, [3 H]substance P binding, or NK1 gene expression in the dorsal horn of the spinal cord between NOP Ϫ/Ϫ and NOP ϩ/ϩ mice. In addition, NOP antagonists decreased the threshold in nociception tests driving spinal substance P neurotransmission. All these findings suggest that the N/OFQ-ergic neuron may play an in vivo inhibitory role on the second-order neurons for primary polymodal substance P-ergic fibers in the spinal cord.

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“…10 Among the small-molecule ligands, Roche has reported an extensive series of NOP agonists based on the spirodecanone (e.g., Ro 64-6198) and hexahydropyrrolopyrrole (I) heterocyclic moieties (Chart 1). 11 NOP antagonists such as the benzimidazolone J113397, 12 the quinoline JTC-801, 13 and recently the phenylpiperidine SB-612111 9a (Chart 1) have also been reported and pharmacologically characterized. Except for JTC-801, almost all smallmolecule ligands contain a common central piperidine core, with a 4-position heterocyclic moiety and a lipophilic group on the piperidine nitrogen.…”

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confidence: 99%

A Novel Series of Piperidin-4-yl-1,3-Dihydroindol-2-ones as Agonist and Antagonist Ligands at the Nociceptin Receptor

et al. 2004

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A series of N-(4-piperidinyl)-2-indolinones were discovered as a new structural class of nociceptin receptor (NOP) ligands. Unlike other previously reported classes of NOP receptor ligands, modifications of the piperidine N substituents afforded both potent agonists and antagonists, with modest selectivities over other opioid receptors. The SAR revealed in this new series will provide important insights for the development of pharmacophores for agonist and antagonist actions at the NOP receptor.The nociceptin receptor (NOP receptor, previously known as the opioid receptor-like receptor ORL1) was discovered in 1994 because of its homology to the opioid receptors. 1 Interestingly, this fourth member of the opioid receptor family did not bind classical opioids with appreciable affinity. Soon after, two groups independently identified its endogenous ligand, a heptadeca-peptide named nociceptin 2 or orphanin FQ (N/OFQ). 3 Since then, the physiological role of the NOP receptor and its ligand N/OFQ has been the focus of intense research. Although both the NOP receptor and its ligand share significant homology with the classical opioid receptors and their ligands, none of the mature experience with the opioid pharmacology can be brought to bear on the study of the NOP-N/OFQ system because none of the known opioid ligands or synthetic opiates bind appreciably to the NOP receptor.The NOP-N/OFQ system has been shown to be involved in pain and analgesia, anxiety, learning and memory, tolerance development, and reward pathways. 4 The ligand N/OFQ has been shown to have a potent anxiolytic effect in rodent models, 5 inhibits release of serotonin and dopamine in reward pathways, 6 and blocks conditioned place preference to morphine, 7 suggesting a role for NOP agonists as anxiolytics and drug abuse treatments. Studies in NOP -/-mice showed that they exhibited improved memory and attention 8a,b and reduced tolerance development to morphine analgesia, 8c suggesting that NOP antagonists could be useful for improving memory and modulating tolerance development when given in combination with potent analgesics such as morphine. We report a new series of NOP ligands based on a 1,3-dihydroindol-2-one heterocyclic scaffold. This series is particularly interesting because subtle structural changes in the nature of the piperidine N-1 substituent resulted in converting potent antagonists into potent agonists with modest selectivities. Thus, unlike the previously reported series of NOP ligands, this new series of indolinone ligands produced both potent NOP agonists and antagonists within the same structural series.Our discovery of this new class of ligands began with the random screening hit 1a (Table 1), which had higher affinity for the μ and κ opioid receptors. Modification of the piperidine N-1 substituent of the lead compound resulted in potent NOP ligands, a trend that has been observed with other reported series of NOP ligands. We first replaced the N-1 benzyl group of 1a with the cyclooctylmethyl group to give 1b. This resu...

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4-Aminoquinolines: Novel Nociceptin Antagonists with Analgesic Activity

Cited by 144 publications

References 23 publications

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)

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)

In Vivo Pain-Inhibitory Role of Nociceptin/Orphanin FQ in Spinal Cord

A Novel Series of Piperidin-4-yl-1,3-Dihydroindol-2-ones as Agonist and Antagonist Ligands at the Nociceptin Receptor

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