In vitro and in vivo pharmacological characterization of J-113397, a potent and selective non-peptidyl ORL1 receptor antagonist

Ozaki, Satoshi; Kawamoto, Hiroshi; Itoh, Yoshiki; Miyaji, Mitsuru; Azuma, Tomoko; Ichikawa, Daisuke; Nambu, Hirohide; Iguchi, Tomoko; Iwasawa, Yoshikazu; Ohta, Hisashi

doi:10.1016/s0014-2999(00)00520-3

Cited by 161 publications

(145 citation statements)

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“…The following NOP ligands are currently available: i) small non peptide molecules, e.g. the agonist Ro 64-6198 [29] and the antagonists J-113397 [46] and SB-612111 [52]; ii) small peptides such as the hexapeptides Ac-RYYRWK-NH 2 and Ac-RYYRIK-NH 2 [19] and the pseudopentadapeptide III-BTD [2]; iii) a large series of N/ OFQ related peptides chemically modified for increasing agonist potency or for reducing or eliminating efficacy. Details about these three classes of NOP ligands can be found in recent review articles such as [53] and [3].…”

Section: Introductionmentioning

confidence: 99%

In vitro and in vivo studies on UFP-112, a novel potent and long lasting agonist selective for the nociceptin/orphanin FQ receptor

et al. 2007

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Abstract[(pF)Phe 4 Aib 7 Arg 14 Lys 15 ]N/OFQ-NH 2 (UFP-112) has been designed as a novel ligand for the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) by combining into the same peptide different chemical modifications reported to increase N/OFQ potency. In vitro data obtained in the electrically stimulated mouse vas deferens demonstrated that UFP-112 behaved as a high potency (pEC 50 9.43) full agonist at the NOP receptor. UFP-112 effects were sensitive to the NOP antagonist UFP-101 but not to naloxone and no longer evident in tissues taken from NOP −/− mice. In vitro half life of UFP-112 in mouse plasma and brain homogenate was 2.6 and 3.5 fold higher than that of N/ OFQ. In vivo, in the mouse tail withdrawal assay, UFP-112 (1-100 pmol, i.c.v.) mimicked the actions of N/OFQ producing pronociceptive effects after i.c.v. administration and antinociceptive effects when given i.t; in both cases, UFP-112 was approx. 100 fold more potent than the natural peptide and produced longer lasting effects. UFP-112 also mimicked the hyperphagic effect of N/OFQ producing a bell shaped dose response curve with the maximum reached at 10 pmol. The hyperphagic effects of N/OFQ and UFP-112 were absent in NOP −/− mice. Equi-effective high doses of UFP-112 (0.1 nmol) and N/OFQ (10 nmol) were injected i.c.v. in mice and spontaneous locomotor activity recorded for 16 h. N/OFQ produced a clear inhibitory effect which lasted for 60 min while UFP-112 elicited longer lasting effects (> 6h). In conscious rats, UFP-112 (0.1 and 10 nmol/kg, i.v.) produced a marked and sustained decrease in heart rate, blood pressure, and urinary sodium excretion and a profound increase in urine flow. Collectively, these findings demonstrate that UFP-112 behaves in vitro and in vivo as a highly potent and selective ligand able to produce full and long lasting activation of NOP receptors.

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Section: Introductionmentioning

confidence: 99%

In vitro and in vivo studies on UFP-112, a novel potent and long lasting agonist selective for the nociceptin/orphanin FQ receptor

et al. 2007

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“…These results agree with rodent studies, indicating that intrathecal substance P causes hyperalgesic effects. 27,30 Intrathecal administration of substance P and N/OFQ both produced a similar degree of hyperalgesic effects, as shown by decreased response latency approximately for 2 to 3 seconds in rodents. 30,39 It has been suggested that intrathecal N/OFQ-induced hyperalgesia may be mediated by tachykinin NK1 receptors in the mouse spinal cord.…”

Section: Discussionmentioning

confidence: 93%

“…As noted, rodent studies have shown that intrathecal DAMGO and substance P produced antinociceptive and pronociceptive effects, respectively. 29,30,41 By using both behavioral end points (ie, antinociception/hyperalgesia and scratching responses), effects of intrathecal DAMGO and substance P were compared with those of intrathecal N/OFQ. Antinociceptive effects of intrathecal N/OFQ were further studied against a noxious stimulus in 2 intensities.…”

Section: Resultsmentioning

confidence: 99%

“…30,39 It has been suggested that intrathecal N/OFQ-induced hyperalgesia may be mediated by tachykinin NK1 receptors in the mouse spinal cord. 39,40 Although intrathecal N/OFQ did not produce hyperalgesic effects like intrathecal substance P in monkeys, more studies are warranted to elucidate the relationship of intrathecal substance P with other neurotransmitter systems in the modulation of nociceptive processing of the primate spinal cord.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacological Studies of NOP Receptor Agonists as Novel Analgesics

Ko¹

2010

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. (From -To) REPORT DATE (DD-MM-YYYY) 01-May-2010 REPORT TYPE Final DATES COVERED PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERDepartment of Pharmacology University of Michigan 1301 MSRB III Ann Arbor, MI 48109-5632 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Material Command SPONSOR/MONITOR'S REPORTFort Detrick, Maryland 21702 NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for public release; distribution unlimited SUPPLEMENTARY NOTES ABSTRACTThe studies proposed in this project will test the hypotheses that in the non-human primate (1) the functions and behavioral effects of the NOP receptor are independent of classical opioid receptors, (2) activation of the NOP receptor produces strong antinociception without abuse liability, and (3) NOP receptor agonists possess a promising therapeutic profile as analgesics compared to mu opioids following repeated administration in primates. Several key findings have been obtained and some have been published. First, intrathecal administration of N/OFQ only produced antinociception in primates. The functional profiles of spinal NOP receptors are different between primates and rodents. Second, intrathecal administration of N/OFQ and other NOP receptor agonists produced antinociception without eliciting itch/scratching responses, indicating that NOP receptor agonists represent a therapeutic target as spinal analgesics. Third, NOP receptor agonists produced antinociceptive effects comparable to clinically used mu opioids such as morphine and alfentanil in three different primate pain models, indicating that the analgesic effectiveness of NOP receptor agonists may be similar to that of mu opioid analgesics in humans. Finally, unlike mu opioids, NOP receptor agonists did not produce reinforcing effects, respiratory depressant, sedation, or itch/pruritic side effects, indicating that NOP receptor agonists may be a new generation of novel analgesics without abuse liability. 1 SUBJECT TERMS INTRODUCTIONProposed studies intend to investigate the potential ...

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“…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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In vitro and in vivo pharmacological characterization of J-113397, a potent and selective non-peptidyl ORL1 receptor antagonist

Cited by 161 publications

References 30 publications

In vitro and in vivo studies on UFP-112, a novel potent and long lasting agonist selective for the nociceptin/orphanin FQ receptor

In vitro and in vivo studies on UFP-112, a novel potent and long lasting agonist selective for the nociceptin/orphanin FQ receptor

Pharmacological Studies of NOP Receptor Agonists as Novel Analgesics

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

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