筑波大学WPI－IIIS長瀬研究室（創薬化学）では、オレキシン作動薬の開発やオピオイドの研究を行っています。

筑波大学　国際統合睡眠医科学研究機構（WPI-IIIS）長瀬研究室（創薬化学）

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研究業績

1. Hino, T.; Kutsumura, N.; Saitoh, T.; Yamamoto, N.; Nagumo, Y.; Mogi, Y.; Watanabe, Y.; Nagase, H.
   “Novel Baeyer-Villiger-type oxidation of 4,5-epoxymorphinan derivatives”
   Tetrahedron Lett. 2021, 63, 152714. (web)

1. Nagumo, Y.; Ueta, Y.; Nakayama, H.; Osaki, H.; Takeuchi, Y.; Uesaka, N.; Kano, M.; Miyata, M.
   “Tonic GABAergic inhibition is essential for nerve injury-induced afferent remodeling in the somatosensory thalamus and ectopic sensations”
   Cell Reports 2020, 31, 107797. (web)
2. Nagumo, Y.; Katoh, K.; Saitoh, T.; Kutsumura, N.; Yamamoto, N.; Ishikawa, Y.; Irukayama-Tomobe, Y.; Ogawa, Y.; Baba, T.; Tanimura, R.; Yanagisawa, M.; Nagase, H.
   “Discovery of attenuation effect of orexin 1 receptor to aversion of nalfurafine: Synthesis and evaluation of D-nor-nalfurafine derivatives and analyses of the three active conformations of nalfurafine”
   Bioorg. Med. Chem. Lett. 2020, 30, 127360. (web)
3. Kutsumura, N.; Koyama, Y.; Saitoh, T.; Yamamoto, N.; Nagumo, Y.; Miyata, Y.; Hokari, R.; Ishiyama, A.; Iwatsuki, M.; Otoguro, K.; Ōmura, S.; Nagase, H.
   “Structure-Activity Relationship between Thiol Group-Trapping Ability of Morphinan Compounds with a Michael Acceptor and Anti-Plasmodium falciparum Activities”
   Molecules 2020, 25, 1112. (web) (Invited Paper)
4. Saitoh, T.; Seki, K.; Nakajima, R.; Yamamoto, N.; Kutsumura, N.; Nagumo, Y.; Irukayama-Tomobe, Y.; Ogawa, Y.; Ishikawa, Y.; Yanagisawa, M.; Nagase, H.
   “Essential structure of orexin 1 receptor antagonist YNT-707, part V: Structure-activity relationship study of the substituents on the 17-amino group”
   Bioorg. Med. Chem. Lett. 2020, 30, 126893. (web)

1. Yamada, D.; Yanagisawa, S.; Yoshizawa, K.; Yanagita, S.; Oka, J.; Nagase, H.; Saitoh, A.
   “Selective agonists of the δ-opioid receptor, KNT-127 and SNC80, act differentially on extinction learning of contextual fear memory in mice”
   Neuropharmacology 2019, 160, 107792. (web)
2. Saitoh, T.; Seki, K.; Nakajima, R.; Yamamoto, N.; Kutsumura, N.; Nagumo, Y.; Irukayama-Tomobe, Y.; Ogawa, Y.; Ishikawa, Y.; Tanimura, R.; Yanagisawa, M.; Nagase, H.
   “Essential structure of orexin 1 receptor antagonist YNT-707, Part IV: The role of D-ring in 4,5-epoxymorphinan on the orexin 1 receptor antagonistic activity”
   Bioorg. Med. Chem. Lett. 2019, 29, 2655-2658. (web)
3. Kutsumura, N.; Inagaki, M.; Kiriseko, A.; Saito, T.
   “Total Synthesis of 3-epi-Juruenolide C”
   Chem. Pharm. Bull. 2019, 67, 594-598. (web)
   selected as a Highlighted paper selected by Editor-in-Chief.
   selected as a Featured Article.
   
4. Yamamoto, N.; Ohrui, S.; Okada, T.; Saitoh, T.; Kutsumura, N.; Nagumo, Y.; Irukayama-Tomobe, Y.; Ogawa, Y.; Ishikawa, Y.; Watanabe, Y.; Hayakawa, D.; Gouda, H.; Yanagisawa, M.; Nagase, H.
   “Essential structure of orexin 1 receptor antagonist YNT-707, Part III: Role of the 14-hydroxy and the 3-methoxy groups in antagonistic activity toward the orexin 1 receptor in YNT-707 derivatives lacking the 4,5-epoxy ring”
   Bioorg. Med. Chem. 2019, 27, 1747-1758. (web) (Invited Paper)
5. Yata, M.; Kutsumura, N.; Nagumo, Y.; Yamamoto, N.; Saitoh, T.; Ishikawa, Y.; Irukayama-Tomobe, Y.; Yanagisawa, M.; Nagase, H.
   “A Novel Rearrangement Reaction of Morphinan to Arylmorphan Skeletons and the Pharmacologies of Arylmorphan Derivatives”
   Heterocycles 2019, 99, 134-144. (web) (Invited Paper)
6. Hirayama, S.; Obayashi, K.; Wada, N.; Ohyama, K.; Fuku, S.; Koyano, K.; Karaki, F.; Itoh, K.; Nagase, H.; Fujii, H.
   “The Practical Synthesis of Dissymmetrical 1,3,5-Trioxazatriquinane Derivatives Comprised of Three Distinct Carbonyl Compounds”
   Heterocycles 2019, 99, 1003-1019. (web) (Invited Paper)
   
7. Kutsumura, N.; Numata, K.; Mosaki, S.; Saito, T.
   “Total Synthesis of Haplacutines B and C”
   Heterocycles 2019, 99, 614-624. (web) (Invited Paper)
   
8. Korkutata, M.; Saitoh, T.; Cherasse, Y.; Ioka, S.; Duo, F.; Qin, R.; Murakoshi, N.; Fujii, S.; Zhou, X.; Sugiyama, F.; Chen, J.-F.; Kumagai, H.; Nagase, H.; Lazarus, M.
   “Enhancing endogenous adenosine A2A receptor signaling induces slow-wave sleep without affecting body temperature and cardiovascular function”
   Neuropharmacol. 2019, 144, 122-132. (web)
9. Sugiyama, A.; Yamada, M.; Furuie, H.; Gotoh, L.; Saitoh, A.; Nagase, H.; Oka, J.; Yamada, M.
   “Systemic administration of a delta opioid receptor agonist, KNT-127, facilitates extinction learning of fear memory in rats”
   J. Pharmacol. Sci. 2019, 139, 174-179. (web)
10. Zhang, Y.; Sugai, T.; Yamamoto, T.; Yamamoto, N.; Kutsumura, N.; Nishiyama, S.; Einaga, Y.; Saitoh, T.; Nagase, H.
    “Oxidative Cleavage of the Acyl-Carbon Bond in Phenylacetone with Electrogenerated Superoxide Anions”
    ChemElectroChem 2019, 6, 4194-4198. (web) (Invited Paper)

1. Kutsumura, N.; Kiriseko, A.; Niwa, K.; Saito, T.
   “Total Syntheses of 3-epi-Litsenolide D2 and Lincomolide A”
   J. Org. Chem. 2018, 83, 11450-11457. (web)
2. Sugiyama, A.; Yamada, M.; Siatoh, A.; Nagase, H.; Oka, J.; Yamada, M.
   “Administration of a delta opioid receptor agonist KNT-127 to the basolateral amygdala has robust anxiolytic-like effects in rats”
   Psychopharmacol. 2018, 235, 2947-2955. (web)
3. Saitoh, A.; Soda, A.; Kayashima, S.; Yoshizawa, K.; Oka, J.; Nagase, H.; Yamada, M.
   “A delta opioid receptor agonist, KNT-127, in the prelimbic medial prefrontal cortex attenuates glial glutamate transporter blocker-induced anxiety-like behavior in mice”
   J. Pharmacol. Sci. 2018, 138, 176-183. (web)
4. Toyama, S.; Shimoyama, N.; Tagaito, Y.; Nagase, H.; Saitoh, T.; Yanagisawa, M.; Shimoyama, M.
   “Nonpeptide Orexin-2 Receptor Agonist Attenuates Morphine-induced Sedative Effects in Rats”
   Anesthesiology 2018, 128, 992-1003. (web)
5. Wang, Y.; Cao, L.; Lee, C.-Y.; Matsuo, T.; Wu, K.; Asher, G.; Tang, L.; Saitoh, T.; Russell, J.; Klewe-Nebenius, D.; Wang, L.; Soya, S.; Hasegawa, E.; Cherasse, Y.; Zhou, J.; Li, Y.; Wang, T.; Zhan, X.; Miyoshi, C.; Irukayama, Y.; Cao, J.; Meeks, J. P.; Gautron, L.; Wang, Z.; Sakurai, K.; Funato, H.; Sakurai, T.; Yanagisawa, M.; Nagase, H.; Kobayakawa, R.; Kobayakawa, K.; Beutler, B.; Liu, Q.
   “Large-scale forward genetics screening identifies Trapa1 as a chemosensor for predator odor-evoked innate fear behaviors”
   Nat. Commun. 2018, 9(2041). (web)
   
6. Ohshita, R.; Kutsumura, N.; Nagumo, Y.; Yamamoto, N.; Saitoh, T.; Hirayama, S, Fujii, H.; Nagase, H.
   “Synthesis of Novel 1,3-Dioxa-5-thiazatriquinane and 1-Oxa-3,5-dithiazatriquinane Derivatives and their Pharmacologies”
   Heterocycles 2018, 97, 687-695. (web) (Invited Paper)
7. Kutsumura, N.; Koyama, Y.; Suzuki, Y.; Tominaga, K.; Yamamoto, N.; Saitoh, T.; Nagumo, Y.; Nagase, H.
   “Favorskii-Type Rearrangement of the 4,5-Epoxymorphinan Skeleton”
   Org. Lett. 2018, 20, 1559-1562. (web)
8. Ohrui, S.; Yamamoto, N.; Saitoh, T.; Kutsumura, N.; Nagumo, Y.; Irukayama-Tomobe, Y.; Ogawa, Y.; Ishikawa, Y.; Watanabe, Y.; Hayakawa, D.; Gouda, H.; Yanagisawa, M.; Nagase, H.
   “Essential structure of orexin 1 receptor antagonist YNT-707, Part II: Drastic effect of the 14-hydroxy group on the orexin 1 receptor antagonistic activity”
   Bioorg. Med. Chem. Lett. 2018, 28, 774-777. (web)
9. Saitoh, A.; Tominaga, H.; Ogawa, Y.; Irukayama-Tomobe, Y.; Yamada, M.; Yanagisawa, M.; Nagase, H.
   “Effects of the delta opioid receptor agonist KNT-127 on electroencephalographic activity in mice”
   Pharmacol. Rep. 2018, 70, 350-354. (web)
10. Tateno, K.; Ogawa, R.; Sakamoto, R.; Tsuchiya, M.; Kutsumura, N.; Otani, T.; Ono, K.; Kawai, H.; Saito, T.
    “Dibenzopyrrolo[1,2-a][1,8]naphthyridines: Synthesis and Structural Modification of Fluorescent L-Shaped Heteroarenes”
    J. Org. Chem. 2018, 83, 690-702. (web)
11. Kutsumura, N.; Okada, T.; Imaide, S.; Fujii, H.; Nagase, H.
    “Acetic Anhydride-Mediated Retro-Ene Reaction via a [4.4.3]Propellane Skeleton Intermediate Containing a Quaternary Ammonium Linkage”
    Synthesis 2018, 50, 4263-4269. (web) (Invited Paper)
12. Saitoh, A.; Suzuki, S.; Soda, A.; Ohashi, M.; Yamada, M.; Oka, J.; Nagase, H.; Yamada, M.
    “The delta opioid receptor agonist KNT-127 in the prelimbic medial prefrontal cortex attenuates veratrine-induced anxiety-like behaviors in mice”
    Behav. Brain Res. 2018, 336, 77-84. (web)

1. Kutsumura, N.; Shibuya, K.; Yamaguchi, H.; Saito, T.
   “n-Butyllithium-promoted regioselective elimination of vicinal bis-triflate having an adjacent ether oxygen”
   Tetrahedron Lett. 2017, 58, 4099-4102. (web)
   selected as a Front Cover (Vol. 58, Issue 43, 2017) of Tetrahedron Letters.
2. Yamamoto, N.; Okada, T.; Harada, Y.; Kutsumura, N.; Imaide, S.; Saitoh, T.; Fujii, H.; Nagase, H.
   “The application of a specific morphinan template to the synthesis of galanthamine”
   Tetrahedron 2017, 73, 5751-5758. (web)
3. Fujii, H.; Shimada, N.; Ohtawa, M.; Karaki, F.; Koshizuka, M.; Hayashida, K.; Kamimura, M.; Makino, K.; Nagamitsu, T.; Nagase, H.
   “Deprotection of silyl ethers by using SO3H silica gel: Application to sugar, nucleoside, and alkaloid derivatives”
   Tetrahedron 2017, 73, 5425-5429. (web)
4. Kutsumura, N.; Ohshita, R.; Horiuchi, J.; Tateno, K.; Yamamoto, N.; Saitoh, T.; Nagumo, Y.; Kawai, H.; Nagase, H.
   “Synthesis of heterocyclic compounds with adamantane-like cage structures consisting of phosphorus, sulfur, and carbon”
   Tetrahedron 2017, 73, 5214-5219. (web)
5. Yamamoto, N.; Ohrui, S.; Okada, T.; Yata, M.; Saitoh, T.; Kutsumura, N.; Nagumo, Y.; Irukayama-Tomobe, Y.; Ogawa, Y.; Ishikawa, Y.; Watanabe, Y.; Hayakawa, D.; Gouda, H.; Yanagisawa, M.; Nagase, H.
   “Essential structure of orexin 1 receptor antagonist YNT-707: Part I Role of the 4,5-epoxy ring for binding with orexin 1 receptor”
   Bioorg. Med. Chem. Lett. 2017, 27, 4176-4179. (web)
6. Kutsumura, N.; Koyama, Y.; Nagumo, Y.; Nakajima, R.; Miyata, Y.; Yamamoto, N.; Saitoh, T.; Yoshida, N.; Iwata, S.; Nagase, H.
   “Antitrichomonal activity of δ opioid receptor antagonists, 7-benzylidenenaltrexone derivatives”
   Bioorg. Med. Chem. 2017, 25, 4375-4383. (web)
7. Watanabe, Y.; Hayashida, K.; Saito, D.; Takahashi, T.; Sakai, J.; Nakata, E.; Kanda, T.; Iwai, T.; Hirayama, S.; Fujii, H.; Yamakawa, T.; Nagase, H.
   “Design and synthesis of novel δ opioid receptor agonists with an azatricyclodecane skeleton for improving blood-brain barrier penetration”
   Bioorg. Med. Chem. Lett. 2017, 27, 3495-3498. (web)
8. Hayashida, K.; Hirayama, S.; Iwai, T.; Watanabe, Y.; Takahashi, T.; Sakai, J.; Nakata, E.; Yamakawa, T.; Fujii, H.; Nagase, H.
   “Novel delta opioid receptor agonists with oxazatricyclodecane structure showing potent agonistic activities”
   Bioorg. Med. Chem. Lett. 2017, 27, 2742-2745. (web)
9. Irukayama-Tomobe, Y.; Ogawa, Y.; Tominaga, H.; Ishikawa, Y.; Hosokawa, N.; Ambai, S.; Kawabe, Y.; Uchida, S.; Nakajima, R.; Saitoh, T.; Kanda, T.; Vogt, K.; Sakurai, T.; Nagase, H.; Yanagisawa, M.
   “Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models”
   Proc. Nat. Acad. Sci. USA 2017, 114, 5731-5736. (web)
10. Hamada, Y.; Tasaki, Y.; Morita, K.; Yamamizu, K.; Narita, M.; Matsuyama, F.; Suzuki, M.; Ikegami, D.; Arakawa, K.; Nagumo, Y.; Kawata, M.; Uezono, Y.; Nagase, H.; Aoki, K.; Yamashita, J. K.; Kuzumaki, N.; Narita, M.
    “The κ-Opioid Receptor Agonist Nalfurafine Enhances the Chemotherapy-induced Survival Advantage in Pancreatic Cancer-bearing Mice”
    Jpn. J. Pharm. Palliat. Care Sci. 2017, 10, 7-12.
11. Lansu, K.; Karpiak, J.; Liu, J.; Huang, X.-P.; McCorvy, J. D.; Kroeze, W. K.; Che, T.; Nagase, H.; Carroll, F. I.; Jin, J.; Shoichet, B. K.; Roth, B. L.
    “In silico design of novel probes for the atypical opioid receptor MRGPRX2″
    Nat. Chem. Biol. 2017, 13, 529-536. (web)
12. Nagase, H.; Yamamoto, N.; Yata, M.; Ohrui, S.; Okada, T.; Saitoh, T.; Kutsumura, N.; Nagumo, Y.; Irukayama-Tomobe, Y.; Ishikawa, Y.; Ogawa, Y.; Hirayama, S.; Kuroda, D.; Watanabe, Y.; Gouda, H.; Yanagisawa, M.
    “Design and Synthesis of Potent and Highly Selective Orexin 1 Receptor Antagonists with a Morphinan Skeleton and their Pharmacologies”
    J. Med. Chem. 2017, 60, 1018-1040. (web)
    
13. Gotoh, L.; Saitoh, A.; Yamada, M.; Fujii, H.; Nagase, H.; Yamada, M.
    “Effects of repeated treatment with a delta opioid receptor agonist KNT-127 on hyperemotionality in olfactory-bulbectomized rats”
    Behav. Brain Res. 2017, 323, 11-14. (web)