Hiroshi Nagase

University of Tsukuba, Tsukuba, Ibaraki, Japan

Are you Hiroshi Nagase?

Claim your profile

Publications (304)747.7 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We designed and synthesized the 1,3,5-trioxazatriquinane derivatives with m-hydroxyphenyl groups. These compounds include the phenethylamine structure within them, which is a common structure observed in morphinan derivatives like morphine. Among the synthesized compounds, (-)-8c with two m-hydroxyphenyl groups selectively bound and exerted full agonist activity toward the κ opioid receptor (KOR). Subcutaneously administered (-)-8c exhibited significant antinociceptive effects via the KOR in a dose-dependent manner. These results suggest the emergence of a novel class of KOR agonist.
    ACS Medicinal Chemistry Letters 08/2014; 5(8):868-72. · 3.07 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We designed and synthesized of 1,3,5-trioxazatriquinanes with o- or p-hydroxyphenyl rings as analogs of the κ opioid receptor agonist SYK-146 with m-hydroxyphenyl groups. Although almost all tested compounds did not bind to the opioid receptors, only 17b (SYK-524) with two o-hydroxyphenyl rings showed moderate or potent binding affinities and exhibited agonistic activities for the three opioid receptor types. Because the basicity of the nitrogen atom in the 1,3,5-trioxazatriquinane structure was predicted to be very low due to the electron withdrawing effect of the three oxygen atoms, SYK-524 was a novel non-morphinan and nonpeptidic opioid universal agonist lacking a basic nitrogen atom.
    Bioorganic & Medicinal Chemistry Letters 08/2014; · 2.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background And PurposeDelta opioid receptor (DOP) activation regulates pain and emotional responses. Ligand-biased agonism at DOP was shown, with differential effects on analgesia, receptor internalization, locomotion and tolerance. KNT-127 is a novel DOP agonist inducing analgesia in chemical pain tests and antidepressant effects in mice. In this study we investigated 1) KNT-127-induced analgesia under chronic inflammatory pain, 2) KNT-127 effects on depression, locomotion and delta-receptor internalization and 3) whether chronic KNT-127 administration induces tolerance to analgesic and antidepressant effects of acute treatment by other DOP agonist.Experimental ApproachInflammatory pain was induced by Complete Freund's Adjuvant-injection into tail or hindpaw, and thermal and mechanical sensitivities were determined in mice. Locomotor and antidepressant-like effects were measured using actimetry and forced swim test, respectively. In vivo KNT-127 selectivity and internalization were assessed using DOP-knockout mice and knock-in mice expressing fluorescent-tagged DOP. KNT-127 was injected acutely at 0.1-10 mg/kg or administered chronically at 5 mg/kg daily over 5-days.Key ResultsAcute KNT-127 reversed inflammatory hyperalgesia, produced an antidepressant-like effect but induced neither hyperlocomotion nor receptor sequestration. Chronic KNT-127 induced tolerance and cross-tolerance to SNC80-induced analgesia, but no tolerance to SNC80-evoked hyperlocomotor or antidepressant-like effects.Conclusions And ImplicationsThe delta opioid KNT-127 induces agonist-specific acute and chronic responses, at both behavioral and cellular levels. It displays activities similar to the other recently reported DOP-agonists, AR-M1000390, ADL5747 and ADL5859, and differs from SNC80. Hence, SNC80 appears to stand out from the other DOP agonists including KNT-127, exhibiting ligand-biased tolerance at the DOP.
    British Journal of Pharmacology 07/2014; · 5.07 Impact Factor
  • ChemInform 06/2014; 45(24).
  • [Show abstract] [Hide abstract]
    ABSTRACT: Indolopropellane 2 was reported to show almost no binding affinity to the δ opioid receptor (DOR) in spite of the fact that 2 has both the propellane fundamental skeleton (message part) with binding ability to the opioid receptors and a possible DOR address structure (indole moiety). We developed the working hypothesis that almost no binding affinity of 2 to the DOR would be derived from its possibly stable bent conformer. To enable the propellane skeleton to adopt an extended conformation which would reasonably interact with the DOR, quinolinopropellanes 3a-d were designed which had an additional pharmacophore, quinoline nitrogen. The calculated binding free energies of ligand-DOR complexes strongly supported our working hypothesis. The synthesized quinolinopropellane 3a was a selective DOR full agonist, confirming our working hypothesis and the results of in silico investigation.
    Bioorganic & medicinal chemistry letters 05/2014; · 2.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We synthesized compounds 4a,c-f,h,i containing the oxazatricyclodecane structure from a novel rearrangement reaction product 2a. All the prepared compounds 4a,c-f,h,i exhibited full agonistic activities for the δ opioid receptor (DOR). Among them, the N-methyl derivative 4c was highly selective, and the most effective DOR agonist in functional assays. Subcutaneous administration of 4c produced dose-dependent and NTI (selective DOR antagonist)-reversible antinociception lacking any convulsive behaviors in the mice acetic acid writhing tests. The N-methyl derivative 4c is expected to be a promising lead compound for selective DOR agonists with a novel chemotype.
    ACS Medicinal Chemistry Letters 04/2014; 5(4):368-372. · 3.07 Impact Factor
  • Bioorganic & Medicinal Chemistry Letters. 01/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Recently, we reported that the δ opioid receptor (DOR) agonist KNT-127 produces anxiolytic-like effects in behaving rats. Here, we report on the roles of DOR subtypes (DOR1 and DOR2) play in mediating KNT-127-induced anxiolytic-like effects. Pretreatment with the DOR2-selective antagonist naltriben (NTB; 0.05 mg/kg, s.c.) completely abolished KNT-127 (3.0 mg/kg, s.c.)-induced anxiolytic-like effects in rats performing the elevated plus-maze task. By contrast, the DOR1-selective antagonist 7-benzylidenenaltrexone (BNTX; 0.5 mg/kg, s.c.) produced no effect at a dose that completely blocked the antinociceptive effects of KNT-127. These findings were also supported by results from a light/dark test and open-field test. We clearly demonstrated that the DOR2-selective antagonist, but not the DOR1-selective antagonist, abolishes the anxiolytic-like effects of the DOR agonist KNT-127, suggesting different roles of these DOR subtypes in anxiety. We propose that DOR2-selective agonists would be good candidates for future development of anxiolytic drugs.
    Neuropharmacology 12/2013; · 4.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Opioids are effective analgesics for the management of moderate to severe cancer pain. Here we show that κ opioid receptor (KOR) agonists act as anti-angiogenic factors in tumors. Treatment with KOR agonists, U50,488H and TRK820, significantly inhibited human umbilical vein endothelial cell (HUVEC) migration and tube formation by suppressing VEGFR2 expression. In contrast, treatment with a μ opioid receptor agonist, DAMGO, or a δ opioid receptor agonist, SNC80, did not prevent angiogenesis in HUVECs. Lewis lung carcinoma (LLC) or B16 melanoma grafted in KOR knockout mice showed increased proliferation and remarkably enhanced tumor angiogenesis compared with those in wild type mice. On the other hand, repeated intraperitoneal injection of TRK820 (0.1-10 μg/kg, b.i.d.) significantly inhibited tumor growth by suppressing tumor angiogenesis. These findings indicate that KOR agonists play an important role in tumor angiogenesis and this knowledge could lead to a novel strategy for cancer therapy.
    Scientific Reports 11/2013; 3:3213. · 5.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We investigated the structure-activity relationship of KNT-127 (opioid δ agonist) derivatives with various 17-substituents which are different in length and size. The 17-substituent in KNT-127 derivatives exerted a great influence on the affinity and agonistic activity for the δ receptor. While the compounds with electron-donating 17-substituents showed higher affinities for the δ receptor than those with electron-withdrawing groups, KNT-127 derivatives with 17-fluoroalkyl groups (the high electron-withdrawing groups) showed high selectivities for the δ receptor among evaluated compounds. In addition, the basicity of nitrogen as well as the structure of the 17-N substituent such as the length and configuration at an asymmetric carbon atom contributed to agonist properties for the δ receptor. Thus, the analog with a 17-(3-ethoxypropyl) group showed the best selectively and potent agonistic activity for the δ receptor among KNT-127 derivatives. These findings should be useful for designing novel δ selective agonists.
    Bioorganic & medicinal chemistry 10/2013; · 2.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: The δ opioid receptor mediates various pharmacological effects such as antinociceptive and antidepressant effects, whereas it does not appear to induce μ opioid-like side effects such as dependence, respiratory depression and constipation. Therefore, the δ opioid receptor is a promising drug target. Areas covered: This review covers literature and patents concerning non-peptidic δ opioid receptor agonists, antagonists, modulators and ligands from 2000 to 2012. Pharmacological effects induced by δ receptor agonists or antagonists are also discussed. Expert opinion: Potential therapeutic effects by δ receptor agonists are antinociceptive, antidepressant, anxiolytic, cardioprotective and neuroprotective effects. Among them, anxiolytic effects are of particular interest because the anxiolytic effects by a δ receptor agonist have been observed in humans. Although non-peptidic δ receptor agonists were reported to show convulsive effects via the δ opioid receptor, some δ receptor agonists are known to produce no convulsive behaviors. Therefore, it may be possible to eliminate convulsion induced by a δ receptor agonist. Many δ receptor antagonists were also reported but there is little new information about pharmacological effects by a δ receptor antagonist. Although detailed results were not revealed, two δ receptor antagonists with μ receptor agonistic or antagonistic properties are in the late stages of the clinical trial.
    Expert Opinion on Therapeutic Patents 05/2013; · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Several derivatives with an azabicyclo[2.2.2]octane skeleton having a 7-amide side chain were synthesized. Compounds that had an electron-donating group exhibited high affinity for the μ opioid receptor while those with a bulky substituent at the 8-nitrogen atom had low affinities for all receptor types. High affinities and selectivities for the κ receptor resulted from the introduction of the longer amide side chain at the 7α-position. Our studies indicate that the orientation of the amide side chain at the 7-position within the azabicyclo[2.2.2]octane skeleton is related to selectivity for the κ receptor.
    Bioorganic & medicinal chemistry 04/2013; · 2.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: O—Si bonds in various alkyl and aryl silyl ethers are efficiently cleaved by a new SO3H silica gel on which alkylsulfonic acid group are immobilized.
    ChemInform 03/2013; 44(11).
  • Hiroshi Nagase, Hideaki Fujii
    [Show abstract] [Hide abstract]
    ABSTRACT: The selective κ opioid receptor agonist nalfurafine was launched in 2009 as an antipruritic drug for patients undergoing hemodialysis. It is the first clinically used compound with high selectivity for the κ opioid receptor. Nalfurafine had a different pharmacological feature from other κ opioid agonists. Nalfurafine induced neither addictive nor aversive effects, whereas other κ agonists such as U-50,488H or salvinorin A produced psychotomimetic effects like dysphoria. Therefore, identification of the essential structural moieties of nalfurafine for binding to the κ opioid receptor was important for elucidation of the pharmacological discrepancies observed with these κ opioid agonists. Based on the investigations of various nalfurafine derivatives, the essential structural moieties of nalfurafine were unveiled. Both the nitrogen substituted by a cyclopropylmethyl group and the 6-amide side chain were indispensable. The phenol ring was important for obtaining strong binding affinities for the opioid receptors, but not indispensable for exerting selectivity for the κ receptor. This structure-activity information is expected to lead to the development of novel κ opioid receptor selective agonists.
    Current pharmaceutical design 02/2013; · 4.41 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study investigated whether ethanol combined with low doses of morphine produces rewarding effects in rats. Ethanol (0.075-1.2 g/kg, intraperitoneal [i.p.]) alone did not induce place preference. A moderate dose (1 mg/kg, s.c.), but not a low dose (0.1 mg/kg), of morphine induced a significant place preference. The combination of ethanol (0.075-0.6 g/kg, i.p.) and 0.1 mg/kg of morphine, as well as low doses of morphine (0.03-0.1 mg/kg, subcutaneous [s.c.]) combined with ethanol (0.3 g/kg, i.p.), induced a significant place preference. The combined effect of ethanol and morphine was significantly attenuated by naloxone (0.3 mg/kg, s.c.), naltrindole (1.0 mg/kg, s.c.), or long-term administration of the dopamine D1 receptor antagonist SCH23390 (1.0 mg/kg/day, s.c.). These results suggest that the rewarding effect induced by ethanol and a low dose of morphine is mediated by activation of the central opioidergic and dopaminergic systems through dopamine D1 receptors.
    Journal of Nippon Medical School 01/2013; 80(1):34-41. · 0.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We previously reported that a δ opioid receptor agonist SNC80 produced potent anxiolytic-like effects in rodents. Recently, we succeeded in synthesizing a novel δ opioid receptor agonist KNT-127. In this study, we investigated the anxiolytic-like effects of KNT-127 using three different rat models of innate anxiety. In an elevated plus-maze test, KNT-127 (0.3, 1, and 3.0 mg/kg, s.c.) significantly and dose-dependently increased the time rats spent in the open arms 30 min after administration. The magnitude of the KNT-127 (3.0 mg/kg, s.c.)-induced anxiolytic-like effects was similar to that produced by diazepam (1.0 mg/kg, s.c.), a benzodiazepine anxiolytic. The anxiolytic-like effects of KNT-127 (3.0 mg/kg, s.c.) were abolished by pretreatment with naltrindole (0.1 mg/kg, s.c.), a selective δ opioid receptor antagonist, suggesting that KNT-127-induced anxiolytic-like effects are mediated by δ opioid receptors. These findings were supported by results obtained from light/dark and open-field tests. Interestingly, in contrast to diazepam (1.0 mg/kg, s.c.), KNT-127 (3.0 mg/kg, s.c.) caused no significant performance changes in the Y-maze test, the ethanol-induced sleeping test, and footprint test. This is the first study to demonstrate that the novel δ opioid receptor agonist KNT-127 produces distinct anxiolytic-like effects in rats, without producing the adverse effects associated with benzodiazepines.
    Neuropharmacology 12/2012; · 4.82 Impact Factor
  • Hiroshi Nagase, Hideaki Fujii
    ChemInform 11/2012; 43(45).
  • [Show abstract] [Hide abstract]
    ABSTRACT: We have previously reported the essential structure of the opioid κ receptor agonist nalfurafine hydrochloride (TRK-820) for binding to the κ receptor. In the course of this study, we focused on the effect of the substituent at 17-N in nalfurafine on the binding affinity for the κ receptor. The exchange of the 17-N substituent in nalfurafine from cyclopropylmethyl to fluoro-substituted alkyl groups, which are strong electron withdrawing substituents, almost completely diminished the binding affinities for the μ and δ opioid receptors, but the binding affinity for the κ receptor was still maintained. As a result, nalfurafine derivatives with 17-fluoro-substituted alkyl groups showed higher selectivities for the κ receptor than did nalfurafine itself. With regard to the κ agonistic activities, the conversion of the 17-N substituent in nalfurafine from cyclopropylmethyl to fluoro-substituted alkyl groups led to the gradual decrease of the agonistic activities in the order corresponding to their binding affinities for the κ receptor. In contrast, the derivative with the bulky 17-isobutyl group showed lower affinity and agonistic activity for the κ receptor than the derivatives with the smaller functional groups. This research suggested that both the electronic property and the steric characteristics of the 17-N substituent would have a great influence on the binding property for the κ receptor.
    Bioorganic & medicinal chemistry letters 10/2012; · 2.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Novel double-capped triplet drugs, which have one pharmacophore unit and two epoxymethano or dimethylepoxymethano structures (termed cap or diMe-cap structures, respectively) were synthesized. Key intermediate oxazoline 16 derived from acetone enabled the effective synthesis of double-capped triplets. SYK-134 (7a) and SYK-135 (8a) with N-cyclopropylmethyl substituent and cap structures showed selectivities for the κ opioid receptor. On the other hand, the N-Me series exhibited selectivities for the μ opioid receptor. The double-capped triplet drugs with diMe-cap structures preferred the μ receptor independently of their N-substituents. SYK-385 (19b), one of the μ-selective double-capped triplet drugs, showed the highest selectivity for the μ receptor among the reported μ-selective nonpeptide ligands.
    Bioorganic & medicinal chemistry letters 10/2012; · 2.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To clarify the essential structures of an opioid κ receptor selective agonist, nalfurafine, for binding to the κ receptor, we designed and synthesized the decahydro(iminoethano)phenanthrene derivatives with an oxygen functionality at the 3-position. The introduction of a hydroxy group to the derivatives increased the affinity and selectivity to the κ receptor regardless of the configuration at the 3-position. However, their affinities were lower than those of nalfurafine with the phenolic hydroxy group. The results suggested that the acidity of the hydroxy group would play an important role in the interaction with the opioid receptor. The low affinities of the 3-keto derivatives indicated that the 3-hydroxy group may participate in the hydrogen bonding with the receptor site not as a hydrogen acceptor but as a hydrogen donor. This is the first experimental evidence for a role as a hydrogen donor for the 3-hydroxy group in morphinans. Furthermore, the κ selectivities in these derivatives with the 6α-amide side chain were affected by the the 3-hydroxy group. The obtained structure-activity relationship information is expected to be useful for the design of more selective ligands for the κ receptor.
    Bioorganic & medicinal chemistry letters 10/2012; · 2.65 Impact Factor

Publication Stats

4k Citations
747.70 Total Impact Points


  • 2013–2014
    • University of Tsukuba
      Tsukuba, Ibaraki, Japan
    • Nippon Medical School
      • Nippon Medical School Hospital
      Tokyo, Tokyo-to, Japan
  • 2005–2014
    • Kitasato University
      • • Department of Pharmacy
      • • Department of Pharmaceutical Sciences
      Edo, Tōkyō, Japan
  • 2012
    • Keio University
      • Department of Physiology
      Tokyo, Tokyo-to, Japan
  • 2011
    • Juntendo University
      Edo, Tōkyō, Japan
  • 2006–2011
    • Hokkaido Pharmaceutical University School of Pharmacy
      Otaru, Hokkaidō, Japan
  • 1996–2004
    • Medical College of Wisconsin
      • Department of Anesthesiology
      Milwaukee, WI, United States
  • 1990–2004
    • Hoshi University
      • • Department of Toxicology
      • • Faculty of Pharmaceutical Sciences
      Shinagawa, Tōkyō, Japan
  • 1992–2003
    • Toray Industries
      Edo, Tōkyō, Japan
  • 1998–2002
    • Toyohashi University of Technology
      Toyohasi, Aichi, Japan
  • 1995–1998
    • The University of Arizona
      • Department of Pharmacology and Toxicology
      Tucson, AZ, United States
  • 1993
    • Kyoto Prefectural University of Medicine
      • Department of Surgery
      Kioto, Kyōto, Japan
    • The University of Tokyo
      • Department of Pharmacy
      Tokyo, Tokyo-to, Japan