Design of agonists and antagonists for opioid receptors based on the structures of endomorphins

• Project/Area Number: 19590112
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Kobe Gakuin University
• Principal Investigator: TSUDA Yuko Kobe Gakuin University, 薬学部, 教授 (10098478)
• Co-Investigator(Kenkyū-buntansha): YUKOI Toshio 神戸学院大学, 薬学部, 教授 (50122255) ; OKADA Yoshio 神戸学院大学, 食品薬品総合科学研究科, 教授 (60068236)
• Project Period (FY): 2007 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2009: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2008: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: エンドモルフィン / オピオイド受容体 / 酵素安定性 / コンフォメーション解析 / 分子設計

Research Abstract

We synthesized the [2',6'-Dimethyl-L-tyrosine1]endomorphin 2 (EM-2) analogues containing proline mimics. Among them, [Dmt1, L-Pip2]EM-2 was potent and selective mu-agonist, while [Dmt1, Aze2]EM-2 was mu/delta-agoinist. [Dmt1, Aze2]EM-2 had a cis/trans equilibrium of ratio 2:1 and cis conformer was predominant in both DMSO or H2 O. The cis [Dmt1, Aze2]EM-2conformers took folded form. The further conformational analyses of the analogues are in progress.

Research Products

• [Journal Article] Deprotection of the indole(N^<ind>)-Formly(For)group on tryptophane employing a new re-agent, N, N'-dimethylethylendiamine(DMEDA)in an aqueous solution. (2009)
  • Author(s): 小田上剛直
  • Journal Title: Chem.Pham.Bull. 57 Pages: 211-213
  • Peer Reviewed
• [Journal Article] Identification of new agonists of urotensin-II from a cyclic peptide library. (2009)
  • Author(s): 小田上剛直
  • Journal Title: Bioorg.Med.Chem. 17 Pages: 6742-6747
  • Peer Reviewed
• [Journal Article] Structural studies of [2, 6-dimethyl-L-tyrosine1] endomorphin-2 analogues containing proline mimics (2008)
  • Author(s): Tsuda, Y., Miyazaki, A., Yamada, T., Isozaki, K., Shimohigashi, Y., Ambo, A., Sasaki, Y., Minoura, K., In, Y., Ishida, T., Okada, Y
  • Journal Title: Peptide Science 2008 Pages: 227-228
  • Peer Reviewed
• [Journal Article] New cyclic somatostatin analogues containing a pyrazinone ring: Importance of Tyr for antiproliferative activity (2008)
  • Author(s): Miyazaki, A., Tsuda, Y., Fukushima, S., Yokoi, T., Vantus, T., Bokonyi, G., Szabo, E., Horvath, A., Keri, G., Okada Y
  • Journal Title: Bioorg. Med. Chem. Lett 18 Pages: 6199-6201
  • Peer Reviewed
• [Journal Article] Synthesis of somatostatin analogues containing C-terminal adamantane and their antiproliferative properties (2008)
  • Author(s): Miyazaki, A., Tsuda, Y., Fukushima, S., Yokoi, T., Vantus, T., Bokonyi, G., Szabo, E., Horvath, A., Keri, G., Okada Y
  • Journal Title: J. Med. Chem 51 Pages: 5121-5124
  • Peer Reviewed
• [Journal Article] Synthesis of endomorphin-2 analogues containing piperidinecarboxylic acid (Pip) and 2-azetidinecarboxylic acid (Aze) (2008)
  • Author(s): Tsuda, Y., Miyazaki, A., Yamada, T., Isozaki, K., Shimohigashi, Y., Ambo, A., Sasaki, Y., Okada, Y
  • Journal Title: Peptide Science 2007 Pages: 267-268
  • NAID: 10021906993
  • Peer Reviewed
• [Journal Article] New cyclic somatostatin analogues containing a pyrazinone ring : Importance of Tyr for antiproliferative activity. (2008)
  • Author(s): 宮崎杏奈
  • Journal Title: Bioorg. Med. Chem. Lett. 18 Pages: 6199-6201
  • Peer Reviewed
• [Journal Article] Synthesis of somatostatin analogues containing C-terminal adamantamine and their antiproliferative properties. (2008)
  • Author(s): 宮崎杏奈
  • Journal Title: J. Med. Chem. 51 Pages: 5121-5124
  • Peer Reviewed
• [Journal Article] Synthesis of opioidmimetics, 3-[H-Dmt-NH(CH2)(m)]-6-[H-Dmt-NH(CH2)(n)]-2(1H)-pyrazinon es, and studies on structure-activity relationships (2007)
  • Author(s): Shiotani, K., Miyazaki A., Li, T., Tsuda, Y., Yokoi, T., Ambo, A., Sasaki, Y., Bryant, S.D., Jinsmaa, Y., Lazarus, L.H., Okada, Y
  • Journal Title: Med. Chem 3 Pages: 583-598
  • Peer Reviewed
• [Journal Article] Design and synthesis of opioidmimetics containing 2', 6'-dimethyl-L-tyrosine and a pyrazinone-ring platform (2007)
  • Author(s): Shiotani, K., Li, T., Miyazaki, A., Tsuda, Y., Yokoi, T., Ambo, A., Sasaki, Y., Bryant, S.D., Lazarus, L.H., Okada, Y
  • Journal Title: Chem. Lett 17 Pages: 5768-5771
  • Peer Reviewed
• [Journal Article] [N-Allyl-Dmt1] Endomorphins are {micro}-opioid receptor antagonists lacking inverse agonist properties (2007)
  • Author(s): Marczak, E.D., Jinsmaa, Y., Li, T., Bryant, S.D., Tsuda, Y., Okada, Y., Lazarus, L. H
  • Journal Title: J. Pharmacol. Exp. Ther 323 Pages: 374-380
  • Peer Reviewed
• [Journal Article] Bifunctional [2', 6'-dimethyl-Ltyrosine1] endomorphin-2 analogues substituted at position 3 with alkylated phenylalanine derivatives yield potent mixed mu-agonist/deltaantagonist and dual mu-agonist/ delta-agonist opioid ligands (2007)
  • Author(s): Li, T., Shiotani, K., Miyazaki, A., Tsuda, Y., Ambo, A., Sasaki, Y., Jinsmaa, Y., Marczak, E., Bryant, S.D., Lazarus, L.H., Okada, Y
  • Journal Title: J. Med. Chem 50 Pages: 2753-2766
  • Peer Reviewed
• [Journal Article] Synthesis and biological profiles of endomorphin-2 analogues containing a conformationally constrained moiety (2007)
  • Author(s): suda, Y., Kawakami, T., Fujita, Y., Yamada, T., Isozaki, K., Shimohigashi, Y., Lazarus, L.H., Okada, Y
  • Journal Title: Peptides 2006 Pages: 128-129
• [Journal Article] Synthesis and binding activities for the opioid receptors of endomorphin and morphiceptin analogs containing conformationally constrained 1-aminocyclolakane-1-carboxylic acids (2007)
  • Author(s): Yamada, T., Hakogi, S., Iino, M., Murashima, T., Miyazawa, T., Tsuda, Y., Kawakami, T., Okada, Y., Isozaki, K., Shimohigashi, T
  • Journal Title: Peptides 2006 Pages: 668-669
• [Journal Article] Design and synthesis of opioidmimetics containing 2',6'-dimethyl-L-trosine and apyrazinone-ring platform (2007)
  • Author(s): 塩谷 公隆
  • Journal Title: Bioorg.Med.Chem.Lett 17 Pages: 5768-5771
  • Peer Reviewed
• [Journal Article] [N-Ally;-Dmt^1]-Endomorphins are{micro}-Opioid receptor agonists lacking inverse asonist properties (2007)
  • Author(s): Marczak ED
  • Journal Title: J.Pharmacol.Exp.Ther 323 Pages: 374-380
  • Peer Reviewed
• [Journal Article] Bifunctional[2',6',dimethl-tyrosine]endomorphin-2 analogues subsituted at position 3 with alkylated phenylalanine derivatives yield potent mixed mu-agonist/delta-antagnist and dual mu-agonist/delta-aeonist opioid ligands (2007)
  • Author(s): Li Tingyou
  • Journal Title: J.Med.Chem 50 Pages: 2753-2766
  • Peer Reviewed
• [Presentation] プロリンミミックを含む[2', 6'-dimethyl-L-tyrosine1] endomorphin 2類似体の酵素安定性とコンフォメーションの検討 (2010)
  • Author(s): 津田裕子, 安保明博, 佐々木友亮, 箕浦克彦, 尹康子, 石田寿昌, 岡田芳男
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
• [Presentation] ソマトスタチン由来ペプチドによるDNA合成酵素阻害活性とヒト由来癌細胞増殖抑制活性への影響 (2010)
  • Author(s): 栗山磯子
  • Organizer: 日本農芸化学会2010年度大会
  • Place of Presentation: 東京大学(東京)
• [Presentation] プロリンミミックを含む[2',6'-dimethl-L-tyrosine^1]endomorphin 2類似体の酵素安定性とコンフォメーションの検討 (2010)
  • Author(s): 津田裕子
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
• [Presentation] 小分子ソマトスタチンアナログのDNAポリメラーゼに対する阻害作用 (2010)
  • Author(s): 宮崎杏奈
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
• [Presentation] Dmt-Ticファマコフォアを含む二価性ペプチドの合成とP糖タンパク質阻害活性 (2010)
  • Author(s): 大勝寛通
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
• [Presentation] μ-オピオイド拮抗剤はアルコールで誘導された抑制性シナプス後電流の振動数の増加を減弱させる (2009)
  • Author(s): 津田裕子
  • Organizer: 第12回ペプチドフォーラム
  • Place of Presentation: 九州工業大学、北九州市
  • Year and Date: 2009-01-23
• [Presentation] The role of fibrinolytic system in tumor progression and developing tumor therapy (2009)
  • Author(s): 石原誠人
  • Organizer: アメリカ癌学会
  • Place of Presentation: Denvor, Colorado, USA
• [Presentation] 臨床応用を目指したペプチド性医薬品の創薬科学研究 (2009)
  • Author(s): 宮崎杏奈
  • Organizer: 国際フロンティア産業メッセ
  • Place of Presentation: 神戸
• [Presentation] ソマトスタチン誘導体の合成:疎水性残基の探索 (2009)
  • Author(s): 奥野恵美子
  • Organizer: 第46回ペプチド討論会
  • Place of Presentation: 北九州国際会議場(北九州)
• [Presentation] Warheadを有する新規plasmin inhibitorsの設計・合成 (2009)
  • Author(s): 手納直規
  • Organizer: 第28回メディシナルケミストリーシンポジウム
  • Place of Presentation: 東京大学(東京)
• [Presentation] [N-allyl-Dmt^1]endomorphinの合成とそれによるアルコール依存性の改善 (2009)
  • Author(s): 津田裕子
  • Organizer: 日本薬学会第129年会
  • Place of Presentation: 京都
• [Presentation] ソマトスタチンアナログの抗腫瘍活性とC末アダマンアミン基の影響 (2008)
  • Author(s): 宮崎杏奈
  • Organizer: 第58回日本薬学会近畿支部大会
  • Place of Presentation: 神戸薬科大学キ
  • Year and Date: 2008-10-25
• [Presentation] Synthesis and biological activities of endomorphin-2 analogues containing proline mimics (2008)
  • Author(s): 津田裕子
  • Organizer: II Workshop“From Endogenous Systems to Medicines"
  • Place of Presentation: Warsaw, Poland
  • Year and Date: 2008-09-06
• [Presentation] Synthesis and biological activities of endomorphin-2 analogues containing proline mimics (2008)
  • Author(s): 津田裕子
  • Organizer: II Workshop "From Endogenous Systems to Medi cines"
  • Place of Presentation: ワルシャワ
  • Year and Date: 2008-09-06
• [Presentation] ynthesis and biological activities of endomorphin-2 analogues containing Pro mimics (2008)
  • Author(s): 津田裕子, 宮崎杏奈, 山田隆巳, 磯崎要, 下東康幸, 安保明博, 佐々木有亮, 箕浦克彦, 尹康子、石田寿昌、岡田芳男
  • Organizer: 第30回European Peptide Symposium
  • Place of Presentation: Helsinki, Finland
• [Presentation] プロリンミミックを含む[2', 6'-dimethyl-L-tyrosine1] endomorphin-2類似体のコンフォメーション解析 (2008)
  • Author(s): 津田裕子, 宮崎杏奈, 山田隆巳, 磯崎要, 下東康幸, 安保明博, 佐々木有亮, 箕浦克彦, 尹康子, 石田寿昌、岡田芳男
  • Organizer: 第45回ペプチド討論会
  • Place of Presentation: 東京
• [Presentation] Synthesis and biological activities of endomorphin analogues containing Pro mimics (2008)
  • Author(s): 津田裕子
  • Organizer: 第30回ヨーロッパペプチドシンポジウム
  • Place of Presentation: ヘルシンキ
• [Presentation] The potent antiproliferative activity of small hydrophobic peptides containing adamantly group (2008)
  • Author(s): 宮崎杏奈
  • Organizer: 第30回ヨーロッパペプチドシンポジウム
  • Place of Presentation: ヘルシンキ
• [Presentation] Multifunctional peptides. Analogues of Tyr-MIF (2008)
  • Author(s): Lipkowski Andrzej
  • Organizer: 第30回ヨーロッパペプチドシンポジウム
  • Place of Presentation: ヘルシンキ
• [Presentation] プロリンミミックを含む[2', 6'-dimethy1-L-tyrosine^1]endomorphin-2類似体のコンフォメーシヨン解析 (2008)
  • Author(s): 津田裕子
  • Organizer: 第45回ペプチド討論会
  • Place of Presentation: 東京
• [Presentation] 芳男:ピペリジンカルボン酸またはアゼチジンカルボン酸を含むエンドモルフィンー2類似体の合成 (2007)
  • Author(s): 津田裕子, 宮崎杏奈, 山田隆巳, 磯崎要, 下東康幸, 安保明博, 佐々木有亮, 岡田芳男
  • Organizer: 第44回ペプチド討論会
  • Place of Presentation: 富山
• [Presentation] Synthesis and biological activity of endomorphin-2 analogues containing Promimcs (2007)
  • Author(s): 津田 裕子
  • Organizer: The 6th Symposium on frontiers in Protein Chemistry and Biotechnology
  • Place of Presentation: Chang Chun,China
• [Patent(Industrial Property Rights)] 新規なオピオイド誘導体 (2010)
  • Inventor(s): 岡田芳男, 津田裕子, 横井利夫
  • Industrial Property Rights Holder: 帝国製薬株式会社
  • Acquisition Date: 2010-03-05