Development of novel, specific heterodimerized opioid agonists with less tolerance and side effects
Project/Area Number |
18K07404
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 51030:Pathophysiologic neuroscience-related
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Research Institution | Jikei University School of Medicine (2020) National Cancer Center Japan (2018-2019) |
Principal Investigator |
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Co-Investigator(Kenkyū-buntansha) |
宮野 加奈子 国立研究開発法人国立がん研究センター, 研究所, 主任研究員 (50597888)
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Project Period (FY) |
2018-04-01 – 2021-03-31
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Project Status |
Completed (Fiscal Year 2020)
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Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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Keywords | オピオイド受容体 / GPCR / 二量体 / オピオイド耐性 / μ/δヘテロマー / μδヘテロマー |
Outline of Final Research Achievements |
Recent progress has shown that agonists for dimerized opioid μ/δ receptors formed by μ and δ receptors are less likely to cause tolerance and side effects. The principal investigator synthesized novel prospective μ/δ compounds and screened them as μ/δ dimer-selective agonists. As a result, we were able to identify four selective agonists with high affinity for μ/δ dimerized receptors but low affinity for μ and δ receptors. Furthermore, ten of new compounds have also been constructed by using four agonists as lead compounds. In the future, by using these candidates, we will conduct animal experiments and carry out for licensing out of optimized compounds to pharmaceutical companies to launch next novel opioids with less side effects.
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Academic Significance and Societal Importance of the Research Achievements |
がんの痛みの軽減等に広く用いられている医療用オピオイド麻薬は副作用が必発であるため、副作用の少ない新規オピオイド製剤の開発が求められている。オピオイドμおよびδ受容体からなる二量体化受容体のアゴニストが副作用の少ないオピオイド製剤となるという基礎研究を元に、現在世界中でμ/δ二量体特異的アゴニストの開発が行われている。今回の研究において、オピオイドμ/δ二量体受容体特異的アゴニストを複数合成することができた。同アゴニストを企業導出することで新規オピオイド製剤の開発の道が開けると信じる。
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Report
(4 results)
Research Products
(51 results)
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[Journal Article] The neurosteroid allopregnanolone sulfate inhibits Nav1.3 α subunit-containing voltage-gated sodium channels, expressed in Xenopus oocytes.2018
Author(s)
Horishita T, Yanagihara N, Ueno S, Okura D, Horishita R, Minami T, Ogata Y, Sudo Y, Uezono Y, Kawasaki T.
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Journal Title
J Pharmacol Sci
Volume: 137
Issue: 1
Pages: 93-97
DOI
Related Report
Peer Reviewed
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[Journal Article] Neuropeptide oxytocin enhances μ opioid receptor signaling as a positive allosteric modulator.2018
Author(s)
Meguro, Y., Miyano, K., Hirayama, S., Yoshida, Y., Ishibashi, N., Ogino, T., Fujii, Y., Manabe, S., Eto, M., Nonaka, M., Fujii, H., Ueta, Y., Narita, M., Sata, N., Yada, T., Uezono, Y.
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Journal Title
J Pharmacol Sci
Volume: 137
Issue: 1
Pages: 67-75
DOI
Related Report
Peer Reviewed
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[Presentation] Molecular characterization and comparison of the effects of several opioid agonists clinically used in Japan - Using the CellKeyTM and internalization assays with stable cells expressing opioid μ;, δ or μ/δ dimerized receptors2018
Author(s)
Fujii, Y., Miyano, K., Oshima, K., Manabe, S., Someya, R., Yoshizawa, K., Morimatsu, H., Iseki, M., Inada, E., Uezono, Y
Organizer
18th World Congress of Basic and Clinical Pharmacology
Related Report
Int'l Joint Research
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