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入鹿山 容子

イルカヤマ ヨウコ  (Yoko Irukayama)

基本情報

所属
千葉大学 真菌医学研究センター 特任講師
学位
博士（医学）(筑波大学)
研究者番号
90312834
J-GLOBAL ID
200901017078388062
researchmap会員ID
1000370168

研究キーワード

 5

研究分野

 1

経歴

 5

受賞

 1

論文

 65
  • Tsuyoshi Saitoh, Mao Amezawa, Jumpei Horiuchi, Yasuyuki Nagumo, Naoshi Yamamoto, Noriki Kutsumura, Ryuichiro Ohshita, Akihisa Tokuda, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Yukiko Ishikawa, Emi Hasegawa, Takeshi Sakurai, Yasuo Uchida, Tetsu Sato, Hiroaki Gouda, Ryuji Tanimura, Masashi Yanagisawa, Hiroshi Nagase
    European journal of medicinal chemistry 240 114505-114505 2022年10月5日  査読有り
    Structurally diverse small compounds are utilized to obtain hit compounds that have suitable pharmacophores in appropriate three-dimensional conformations for the target drug receptors. We have focused on the 1,3,5-trioxazatriquinane skeleton, which has a rigid bowl-like structure enabling the diverse orientation of side chain units, leading to a novel small-scale focused library based on the skeleton. In the library screening for the orexin receptor, some of the compounds showed orexin receptor antagonistic activity with a high hit rate of 7%. By optimizing the hit compounds, we discovered a potent dual orexin receptor antagonist, 38b, and a selective orexin 1 receptor antagonist, 41b carrying the same plane structure. Both compounds showed reasonable brain permeability and beneficial effects when administered intraperitoneally to wild-type mice. Docking simulations of their eutomers, (-)-38b and (+)-41b, with orexin receptors suggested that the interaction between the 1,3,5-trioxazatriquinane core structure and the hydrophobic subpocket in orexin receptors enables a U-shape structure, which causes tight van der Waals interactions with the receptors similar to SB-334867, a selective orexin 1 receptor antagonist. These results indicate that the library approach utilizing the 1,3,5-trioxazatriquinanes bearing multiple effective residues (TriMERs) might be useful for the hit discovery process targeting not only opioid and orexin receptors but other G-protein coupled receptors.
  • Keita Iio, Tsuyoshi Saitoh, Ryuichiro Ohshita, Tsubasa Hino, Mao Amezawa, Yoshiaki Takayama, Yasuyuki Nagumo, Naoshi Yamamoto, Noriki Kutsumura, Yoko Irukayama-Tomobe, Yukiko Ishikawa, Ryuji Tanimura, Masashi Yanagisawa, Hiroshi Nagase
    Bioorganic & medicinal chemistry letters 60 128555-128555 2022年3月15日  査読有り
    A novel series of 1-amino-tetralin derivatives were designed and synthesized based on the putative binding mode of the naphthalene-type orexin receptor agonist 5 and their agonist activities against orexin receptors were evaluated. The introduction of N-methyl-(3-methoxyphenyl)acetamide unit onto the 1-amino-tetralin skeleton remarkably enhanced the potency of the agonist. The asymmetric synthesis of 6 revealed that (-)-6 having a (S)-1-amino-tetralin skeleton showed a OX2R selective agonist activity (EC50 = 2.69 nM for OX2R, OX1R/OX2R = 461) yet its enantiomer (R)-(+)-6 showed a potent OX1/2R dual agonist activity (EC50 = 13.5 nM for OX1R, 0.579 nM for OX2R, OX1R/OX2R = 23.3). These results suggested that upward orientation of the amide side chain against the tetralin scaffold (S-configuration) would be selective for OX2R activation, and the downward orientation (R-configuration) would be significant for dual agonist activity. To our best knowledge, there have been no reports thus far that the stereochemistry of one carbon center on the agonist structure regulates the orexin receptor selectivity. Our results would provide important information for the development of OX1R selective agonists.
  • Koki Katoh, Naoshi Yamamoto, Yukiko Ishikawa, Yoko Irukayama-Tomobe, Ryuji Tanimura, Tsuyoshi Saitoh, Yasuyuki Nagumo, Noriki Kutsumura, Masashi Yanagisawa, Hiroshi Nagase
    Bioorganic & medicinal chemistry letters 59 128527-128527 2022年3月1日  査読有り
    To investigate the contribution of hydrogen bonding between the 14-hydroxy group and the 6-amide chain on the binding affinity of nalfurafine toward KOR and OX1R, we prepared the 14-H and 14-dehydrated nalfurafine and their five-membered D-ring nalfurafine (D-nor-nalfurafine) derivatives. The 14-H and 14-dehydrated nalfurafine derivatives showed almost the same affinity for KOR as nalfurafine and more potent affinity for OX1R. On the other hand, 14-H and 14-dehydrated D-nor-nalfurafine derivatives showed weak affinity for KOR and almost no affinity for OX1R. The conformational analyses suggested that the 6-amide chains of the nalfurafine derivatives are mainly oriented just at or downward from the C-ring, while those of the D-nor-nalfurafine derivatives were mainly oriented toward the upper side of the C-ring even in the absence of the 14-hydroxy group. We postulated that the ion-dipole interaction between the 6-amide and the 16-nitrogen might stabilize the upwardly oriented 6-amide group. These results suggested that the 14-hydroxy group and the ion-dipole interaction would play important roles in the orientation of the 6-amide group, which might control the affinity between KOR and OX1R.
  • Tsubasa Hino, Tsuyoshi Saitoh, Yasuyuki Nagumo, Naoshi Yamamoto, Noriki Kutsumura, Yoko Irukayama-Tomobe, Yukiko Ishikawa, Ryuji Tanimura, Masashi Yanagisawa, Hiroshi Nagase
    Bioorganic & medicinal chemistry letters 59 128530-128530 2022年3月1日  査読有り
    A novel series of naphthalene derivatives were designed and synthesized based on the strategy focusing on the restriction of the flexible bond rotation of OX2R selective agonist YNT-185 (1) and their agonist activities against orexin receptors were evaluated. The 1,7-naphthalene derivatives showed superior agonist activity than 2,7-naphthalene derivatives, suggesting that the bent form of 1 would be favorable for the agonist activity. The conformational analysis of 1,7-naphthalene derivatives indicated that the twisting of the amide unit out from the naphthalene plane is important for the enhancement of activity. The introduction of a methyl group on the 2-position of 1,7-naphthalene ring effectively increased the activity, which led to the discovery of the potent OX2R agonist 28c (EC50 = 9.21 nM for OX2R, 148 nM for OX1R). The structure-activity relationship results were well supported by a comparison of the docking simulation results of the most potent derivative 28c with an active state of agonist-bound OX2R cryo-EM SPA structure. These results suggested important information for understanding the active conformation and orientation of pharmacophores in the orexin receptor agonists, which is expected as a chemotherapeutic agent for the treatment of narcolepsy.
  • Koki Katoh, Noriki Kutsumura, Naoshi Yamamoto, Yasuyuki Nagumo, Tsuyoshi Saitoh, Yukiko Ishikawa, Yoko Irukayama-Tomobe, Ryuji Tanimura, Masashi Yanagisawa, Hiroshi Nagase
    Bioorganic & medicinal chemistry letters 59 128550-128550 2022年3月1日  査読有り
    The five-membered D-ring nalfurafine (d-nor-nalfurafine) derivatives with a 16-sulfonamide group were synthesized. Conversion of the 16-cyclopropylmethyl group to the 16-benzenesulfonamide group in the d-nor-nalfurafine derivatives drastically improved the orexin 1 receptor (OX1R) antagonist activities. The intramolecular hydrogen bond between the 14-hydroxy and the 16-sulfonamide groups may play an important role in increasing the probability that the 6-amide group would be located at the lower side of the C-ring, leading to an active conformation for OX1R. The assay results and the conformational analyses of the 14-OH, 14-H, and 14-dehydrated d-nor-nalfurafine derivatives suggested that the 14- and 16-substituents of the d-nor-nalfurafine derivatives had a greater effect on the affinities for the OX1R than did the 14- and 17-substituents of nalfurafine derivatives.
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MISC

 55
  • SUZUKI N, MIYAUCHI T, TOMOBE Y, MATSUMOTO H, GOTO K, MASAKI T, FUJINO M
    Biochem. Biophys. Res. Commun. 167(3) 941-7 1990年3月30日  
  • T Miyauchi, T Ishikawa, Y Tomobe, M Yanagisawa, S Kimura, Y Sugishita, I Ito, K Goto, T Masaki
    Hypertension (Dallas, Tex. : 1979) 14(4) 427-34 1989年10月  
    Endothelin, an endothelium-derived vasoconstrictor peptide, and angiotensin II were intravenously injected into the femoral vein of normotensive Wistar-Kyoto (WKY) rats that had been anesthetized with urethane. Blood pressure and heart rate were recorded from a cannula inserted into the carotid artery. All experiments were carried out after treatment with adrenergic and cholinergic antagonists. Endothelin showed a potent, dose-dependent pressor action. The dose-response relations for the increase in blood pressure of rats receiving endothelin were comparable with those of rats receiving angiotensin II. However, endothelin showed far more long-lasting effects. Endothelin-induced responses consisted of three phases: a rapid and transient depressor phase and then two phases of pressor (transient and long-lasting) response. Nicardipine (0.1 mg/kg), a dihydropyridine Ca2+ channel blocker, markedly attenuated the slow phase of the pressor response but only slightly attenuated the rapid one. The pressor action of endothelin was not inhibited by continuous infusions of saralasin, which almost abolished the angiotensin II-induced pressor response. Endothelin-induced pressor response was also not attenuated by indomethacin, a prostaglandin synthesis inhibitor. These data provide evidence that endothelin produces a unique, potent, and long-lasting pressor response, which appears to be in part related to the activation of Ca2+ channels. In 12-week-old spontaneously hypertensive rats (SHR), the maximal pressor response to endothelin was slightly but significantly greater than that in age-matched WKY rats, but the dose dependency of the response was approximately consistent with that in WKY rats.(ABSTRACT TRUNCATED AT 250 WORDS)
  • Y Tomobe, T Miyauchi, A Saito, M Yanagisawa, S Kimura, K Goto, T Masaki
    European journal of pharmacology 152(3) 373-4 1988年8月2日  
  • M Yanagisawa, H Kurihara, S Kimura, Y Tomobe, M Kobayashi, Y Mitsui, Y Yazaki, K Goto, T Masaki
    Nature 332(6163) 411-5 1988年3月31日  
    An endothelium-derived 21-residue vasoconstrictor peptide, endothelin, has been isolated, and shown to be one of the most potent vasoconstrictors known. Cloning and sequencing of preproendothelin complementary DNA shows that mature endothelin is generated through an unusual proteolytic processing, and regional homologies to a group of neurotoxins suggest that endothelin is an endogenous modulator of voltage-dependent ion channels. Expression of the endothelin gene is regulated by several vasoactive agents, indicating the existence of a novel cardiovascular control system.
  • J. Pharmacol. Exp. Ther. 242(2) 666-72 1987年8月  

書籍等出版物

 5

主要な講演・口頭発表等

 26
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担当経験のある科目(授業)

 1
  • 薬理学  (筑波大学医学群医学類、医療科学類)

所属学協会

 1

共同研究・競争的資金等の研究課題

 12
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産業財産権

 6
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