Discovery of the First Potent and Selective Small Molecule Opioid Receptor-like (ORL1) Antagonist:  1-[(3R,4R)-1-Cyclooctylmethyl-3- hydroxymethyl-4-piperidyl]-3-ethyl- 1,3-dihydro-2H-benzimidazol-2-one (J-113397)

Kawamoto, Hiroshi; Ozaki, Satoshi; Itoh, Yoshiki; Miyaji, Mitsuru; Arai, Satoru; Nakashima, Hiroshi; Kato, Tetsuya; Ohta, Hisashi; Iwasawa, Yoshikazu

doi:10.1021/jm990517p

Cited by 203 publications

(135 citation statements)

References 21 publications

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“…Indeed, Florin and colleagues (1996) suggested that motor suppression at high doses of OFQ/N might be explained by non-specific binding of OFQ/N to kappa opioid receptors. However, we found that the action of OFQ/N on cocaine-induced motor stimulation and behavioral sensitization was blocked by J-113397, an ORL-1 receptor antagonist (Kawamoto et al 1999), indicating that OFQ/N's actions in this regard are mediated via a specific interaction with the ORL-1 receptor.…”

Section: Discussionmentioning

confidence: 80%

“…The specificity of OFQ/N's effect on cocaine-induced behavioral sensitization was examined using J-113397, an ORL-1 receptor antagonist (Kawamoto et al 1999). Rats were habituated to the testing chambers for 1 h and thereafter treated with vehicle [V; 20% dimethyl sulfoxide, (DMSO)] or J-113397 (J; 30 nmol, ICV).…”

Section: Methodsmentioning

confidence: 99%

“…Since rapid tolerance develops to the action of OFQ/N (Devine et al 1996b), the present study was designed to revisit the question by examining the effect of OFQ/N on cocaine-induced behavioral sensitization using an escalating dosing regimen of OFQ/N administered either intracerebroventricularly (ICV) or directly into the VTA. The specificity of OFQ/N's effects was determined using the ORL-1 receptor antagonist, J-113397 (Kawamoto et al 1999). Furthermore, the effect of OFQ/ N on the context-independent component of cocaine sensitization was also evaluated.…”

Section: Introductionmentioning

confidence: 99%

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Orphanin FQ/nociceptin blocks cocaine-induced behavioral sensitization in rats

et al. 2002

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Rationale-Orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the opioid receptor-like (ORL-1) receptor, shows similarities to dynorphin A (1−17) in structure and functions. Dynorphin and other kappa opioid receptor agonists have been shown to block cocaine sensitization.Objective-The present study was designed to examine the ability of OFQ/N to block cocaineinduced behavioral sensitization.Methods-Rats were habituated to testing chambers for 1 h, injected with artificial cerebrospinal fluid (aCSF) or OFQ/N (15 nmol) followed by saline or cocaine (20 mg/kg) and locomotor activity was measured for a further 1 h. Rats were treated similarly for the next 2 days except the dose of OFQ/N was doubled on each subsequent day. Rats were then challenged with cocaine (7.5 mg/kg) in the absence of OFQ/N on day 8. The specificity of OFQ/N's action was examined in the presence of J-113397 (30 nmol), an ORL-1 receptor antagonist. The ability of OFQ/N to block the contextindependent component of cocaine sensitization was also tested wherein rats were treated in their home cages on days 1−3. Finally, the effect of intra-VTA OFQ/N administration on cocaine sensitization was examined.Results-Sensitization did not develop in rats repeatedly treated with OFQ/N, via either route of administration, prior to cocaine administration on days 1−3. The inhibitory effect of OFQ/N was not dependent on context and was blocked by pretreatment with J-113397.Conclusion-Our results indicate that OFQ/N blocks cocaine-induced behavioral sensitization through activation of the ORL-1 receptor and that the VTA may be one of the substrates for this action of OFQ/N.

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Section: Discussionmentioning

confidence: 80%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Orphanin FQ/nociceptin blocks cocaine-induced behavioral sensitization in rats

et al. 2002

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“…The Banyu compound 1-[1-cyclooctylmethyl-4-piperidyl]-1,3-dihydro-2H-benzimidazol-2-one (J-1, Fig. 1) was synthesized in our laboratory by the literature method (Kawamoto et al, 1999).…”

Section: Methodsmentioning

confidence: 99%

“…1). The group from Banyu described a high affinity and selective ORL1 receptor antagonist, 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397), obtained by extensive modification of a lead compound identified by screening (Kawamoto et al, 1999;Ozaki et al, 2000). High affinity agonists, on the other hand, were reported by Hoffman La Roche (Wichmann et al, 1999;Rover et al, 2000) and Novo Nordisk (Thomsen and Hohlweg, 2000).…”

Section: Introductionmentioning

confidence: 99%

Characterization of opiates, neuroleptics, and synthetic analogs at ORL1 and opioid receptors

Zaveri

Polgar

Olsen

et al. 2001

European Journal of Pharmacology

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Nociceptin/orphanin FQ (N/OFQ) was recently identified as the endogenous ligand for the opioidreceptor like (ORL1) receptor. Although the ORL1 receptor shows sequence homology with the opioid receptors, the nociceptin/ORL1 ligand-receptor system has very distinct pharmacological actions compared to the opioid receptor system. Recently, several small-molecule ORL1 receptor ligands were reported by pharmaceutical companies. Most of these ligands had close structural similarities with known neuroleptics and opiates. In this study, we screened several available neuroleptics and opiates for their binding affinity and functional activity at ORL1 and the opioid receptors. We also synthesized several analogs of known opiates with modified piperidine Nsubstituents in order to characterize the ORL1 receptor ligand binding pocket. Substitution with the large, lipophilic cyclooctylmethyl moiety increased ORL1 receptor affinity and decreased μ receptor affinity and efficacy in the fentanyl series of ligands but had a different effect in the oripavine class of opiate ligands. Our results indicate that opiates and neuroleptics may be good starting points for ORL1 receptor ligand design, and the selectivity may be modulated by appropriate structural modifications.

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Narcotic Analgesics

Aldrich

Vigil‐Cruz

2003

Burger's Medicinal Chemistry and Drug Discovery

147

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Narcotic analgesics such as morphine have been the mainstay for the treatment of severe pain, although these drugs are associated with serious adverse effects, most notably addiction liability and respiratory depression. Therefore there has been an intensive effort to find new therapeutic agents that retain the effectiveness of morphine, but do not have its undesired side effects. Compounds have been identified from a wide variety of chemical classes, from the rigid morphinan alkaloids to the flexible phenylpiperidines and the opioid peptides, which have affinity for opioid receptors. In recent years considerable effort has focused on identifying ligands, both agonists and antagonists, with affinity for delta (δ) and kappa (κ) opioid receptors as pharmacological tools and as potential therapeutic agents that would not have the side‐effect profile of morphine and other agonists that interact with mu (μ) opioid receptors. After the identification of the closely related opioid receptor‐like (ORL1) receptor and its endogenous ligand orphanin FQ/nociceptin, there has been considerable effort directed toward identifying agonists and antagonists for this receptor as well. This review discusses the structure‐activity relationships for each of the major classes of compounds that interact with the opioid receptors, along with ligands for the ORL1 receptors.

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Discovery of the First Potent and Selective Small Molecule Opioid Receptor-like (ORL1) Antagonist: 1-[(3R,4R)-1-Cyclooctylmethyl-3- hydroxymethyl-4-piperidyl]-3-ethyl- 1,3-dihydro-2H-benzimidazol-2-one (J-113397)

Cited by 203 publications

References 21 publications

Orphanin FQ/nociceptin blocks cocaine-induced behavioral sensitization in rats

Orphanin FQ/nociceptin blocks cocaine-induced behavioral sensitization in rats

Characterization of opiates, neuroleptics, and synthetic analogs at ORL1 and opioid receptors

Narcotic Analgesics

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