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

2009 Fiscal Year Final Research Report

• 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
• 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] 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
  • 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
• [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
  • Year and Date: 20100328-20100330
• [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
  • Year and Date: 20081029-20081031
• [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
  • Year and Date: 20080831-20080905
• [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] 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
  • Year and Date: 20071107-20071109
• [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
  • Industrial Property Number: 特許(登録No.)4467985
  • Acquisition Date: 2010-03-05