Synthetic Studies on Poison-frog Alkaloids As Antagonists on nicotinic Acetylcholine Receptors

• Project/Area Number: 17590004
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Chemical pharmacy
• Research Institution: University of Toyama
• Principal Investigator: TOYOOKA Naoki University of Toyama, 大学院・医学薬学研究部, 准教授 (10217565)
• Co-Investigator(Kenkyū-buntansha): TSUNEKI Hiroshi 富山大学, 大学院・医学薬学研究部, 准教授 (20332661) ; SASAOKA Toshiyasu 富山大学, 大学院・医学薬学研究部, 教授 (00272906)
• Project Period (FY): 2005 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,100,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥600,000); Fiscal Year 2008: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2005: ¥500,000 (Direct Cost: ¥500,000)
• Keywords: 毒ガエルアルカロイド / ニコチン受容体 / 179 / 207E / ヒドロキシインドリチジン / monomorine I / 231C / 221I / epi-193E / 233A / 235U / 251AA / インドリチジン / 251N / 221K / NIH / 5,8位置換インドリチジン

Research Abstract

毒ガエルアルカロイド類の柔軟で効率的な合成研究を実施し、5, 8位置換インドリチジン、1, 4位置換キノリチジンおよび5, 8位置換6, 7-デヒドロインドリチジンの合成を達成した。これにより、数種のアルカロイドの絶対配置、相対配置を確定した。また、提出構造の誤りを指摘し、訂正構造式の提案を行った。さらに、脳内主要ニコチン受容体に対して、これら毒ガエルアルカロイド類がサブタイプ選択的に抑制作用を示すことも明らかにした。

Research Products

• [Journal Article] Synthesis, Determination of the Absolute Stereochemistry, and Evaluations at the Nicotinic Acetylcholine Receptors of a Hydroxy-indolizidine Alkaloid from the Ant (2009)
  • Author(s): Zhou, D. ; Toyooka, N.* ; Nemoto, H. ; Yamaguchi, K. ; Tsuneki, H. ; Wada, T. ; Sasaoka, T. ; Sakai, H. ; Tezuka, Y. ; Kadota, S. ; Jones, T.H. ; Garraffo, H.M. ; Spande, T.F. ; Daly, J.W.
  • Journal Title: Myrmicaria melanogaster Heterocycles 79 Pages: 565-571
  • Peer Reviewed
• [Journal Article] First Enantioselective Synthesis of a Hydroxyindolizidine Alkaloid from the Ant (2009)
  • Author(s): Toyooka, N.* ; Zhou, D. ; Nemoto, H. ; Tezuka, Y. ; Kadota, S. ; Jones, T.H. ; Garraffo, H.M. ; Spande, T.F. ; Daly, J.W.
  • Journal Title: Myrmicaria melanogaster Synlett Pages: 1894-1896
  • Peer Reviewed
• [Journal Article] Synthesis, Determination of the Absolute Stereochemistry, and Evaluations at the Nicotinic Acetylcholine Receptors of a Hydroxyindolizidine Alkaloid from the Ant Myrmicaria melanogaster (2009)
  • Author(s): Zhou, D., Tovooka. N., Nemoto, H., Yamaguchi, K., Tsuneki, H., Wada, T., Sasaoka, T., Sakai, H., Tezuka, Y., Kadota, S., Jones, T. H., Garraffo, H. M., Spande, T. F., Daly, J. W.
  • Journal Title: Heterocycles 79 Pages: 565-571
  • Peer Reviewed
• [Journal Article] Nemoto, H Enantioselective Syntheses of(-)-and(+)-Monomorine I (2008)
  • Author(s): Toyooka, N.* ; Zhou, D.
  • Journal Title: J. Org. Chem 73 Pages: 4575-4577
  • Peer Reviewed
• [Journal Article] Synthesis of the Proposed Structure of Poison-Frog Alkaloids 179 and 207Eand Their Inhibitory Effects on Neuronal Nicotinic Acetylcholine Receptors (2008)
  • Author(s): Toyooka, N.* ; Zhou, D. ; Kobayashi, S. ; Tsuneki, H. ; Wada, T. ; Sakai, H. ; Nemoto, H. ; Sasaoka, T. ; Tezuka, Y. ; Subehan ; Kadota, S. ; Garraffo, H.M. ; Spande, T.F. ; Daly, J.W.
  • Journal Title: Synlett Pages: 61-64
  • Peer Reviewed
• [Journal Article] Synthesis of the Proposed Structure of Poison-Frog Alkaloids 179 and 207E and Their Inhibitory Effects on Neuronal Nicotinic Acetylcholine Receptors (2008)
  • Author(s): Toyooka, N., Zhou, D., Kobaya shi, S., Tsuneki, H., Wada, T., Sakai, H., Nemoto, H., Sasaoka, T., Tezuka, Y., Subehan, Kadota, S., Garraffo, H. M., Spande, T. F., Daly, J. W.
  • Journal Title: Synlett Pages: 61-64
  • Peer Reviewed
• [Journal Article] Enantioselective Syntheses of (-)-and (+)-Monomorine I (2008)
  • Author(s): Toyooka, N., Zhou D., Nemoto, H.
  • Journal Title: J. Org. Chem. 73 Pages: 4575-4577
  • Peer Reviewed
• [Journal Article] First Enantioselective Synthesis of a Hydroxyindolizidine Alkaloid from the Ant Myrmicaria melanogaster (2008)
  • Author(s): Toyooka. N., Zhou, D., Nemot, H., Tezuka, Y., Kadota, S., Jones, T. H., Garraffo, H. M., Spande, T. F., Daly, J. W.
  • Journal Title: Synlett Pages: 1894-1896
  • Peer Reviewed
• [Journal Article] Synthesis of Poison-frog Alkaloids and Their Pharmacological Effects at Neuronal Nicotinic Acetylcholine Receptors (2007)
  • Author(s): Toyooka, N.* ; Tsuneki, H. ; Kobayashi, S. ; Dejun, Z. ; Kawasaki, M. ; Kimura, K. ; Sasaoka, T. ; Nemoto, H.
  • Journal Title: Current Chemical Biology 1 Pages: 97-114
  • Peer Reviewed
• [Journal Article] Flexible Synthesis of Poison-frog Alkaloids of the 5, 8-Disubstituted Indolizidine-class. II: Synthesis of(-)-209B, (-)-231C, (-)-233D, (-)-235B', (-)-221I, and an Epimer of 193E and Pharmacological Effects at Neuronal Nicotinic Acetylcholine Receptors (2007)
  • Author(s): Kobayashi, S. ; Toyooka, N.* ; Zhou, D. ; Tsuneki, H.* ; Wada, T. ; Sasaoka, T. ; Sakai, H. ; Nemoto, H. ; Garraffo, H.M. ; Spande, T.F. ; Daly, J.W.
  • Journal Title: Beilstein J. Org. Chem 3 Pages: 30-30
  • Peer Reviewed
• [Journal Article] Flexible Synthetic Routes to Poison-frog Alkaloids of the 5,8- Disubstituted Indolizidine-class. I.: Synthesis of Common Lactam Chiral Building Blocks and Application to the Synthesis of(-)-203A, (-)-205A, and(-)-219F (2007)
  • Author(s): Toyooka, N.* ; Zhou, D. ; Nemoto, H. ; Garraffo, H.M. ; Spande, T.F. ; Daly, J.W.
  • Journal Title: Beilstein J. Org. Chem 3 Pages: 29-29
  • Peer Reviewed
• [Journal Article] Synthesis of Poison-frog Alkaloids 233A, 235U, and 251AA and Their Inhibitory Effects on Neuronal Nicotinic Acetylcholine Receptors (2007)
  • Author(s): Toyooka, N.* ; Kobayashi, S. ; Zhou, D. ; Tsuneki, H. ; Wada, T. ; Sakai, H. ; Nemoto, H. ; Sasaoka, T. ; Garraffo, H.M. ; Spande, T.F. ; Daly, J.W.
  • Journal Title: Bioorg. Med. Chem. Lett 17 Pages: 5872-5875
  • Peer Reviewed
• [Journal Article] Synthesis of Poison-frog Alkaloids 233A,235U, and 251AA and Their Inhibitory Effbcts on Neuronal Nicotinic Acetyicholine Receptors (2007)
  • Author(s): Toyooka, N.^*; Kobayashi, S.; Zhou, D.; Tsuneki, H.; Wada, T.; Sakai, H.; Nemoto, H.; Sasaoka, T.; Garraffo, H. M.; Spande, T. F, ; Daly, J. W.
  • Journal Title: Bioorg. Med. Chem. Lett 17 Pages: 5872-5875
  • Peer Reviewed
• [Journal Article] Flexlble Synthetic Routes to Poison-frog Alkaloids of the 5,8-Disubsti tuted Indolizidine-class. I.: Synthesis of Common Lactam Chlrai Building Blocks and Applicatlon to the Synthesis of(-)-203A,(-)-205A, and(-)-219F (2007)
  • Author(s): Tovooka, N.^*; Zhou, D.; Nemo to, H.; Garraffo, H. M.; Spande, T. F.; Daly, J. W.
  • Journal Title: Beilstein J. Org. Chem 3(online journal) Pages: 29-29
  • Peer Reviewed
• [Journal Article] Rexlble Synthesis of Poison-frog Aikaloids of the 5,8-Disubstituted Indolizidine-class. II: Synthesis of(-)-209B, (-)-231C, (-)-233D, (-)-235B'',(-)-221I, and an Epimer of 193E and Pharmacological Effects at Neuronal Nicotinlc Acetylcholine Receptors (2007)
  • Author(s): Kobayashl, S.; Toyooka, N.^*; Zhou, D.; Tsuneki, H.; Wada, T.; Sasaoka, T.; Sakai, H.; Nemoto, H.; Garraffo, H. M.; Spande, T. F.; Daly, J. W.
  • Journal Title: Beilstein J. Org. Chem 3(online journal) Pages: 30-30
  • Peer Reviewed
• [Journal Article] Synthesis of Poison-frog Alkaloids and Their Pharmacolo gical Effects at Neuronal Nicotinic Acetylcholine Receptors (2007)
  • Author(s): Toyooka, N.^*; Tsuneki, H.; Kobayashi, S.; Dejun, Z.; Kawasaki, M.; Kimura, K.; Sasaoka, T.; Nemoto H.
  • Journal Title: Current Chemical Biology 1 Pages: 97-114
  • Peer Reviewed
• [Journal Article] 毒ガエルアルカロイドの合成とニコチン受容体に対する活性評価 (2006)
  • Author(s): 豊岡尚樹*、根本英雄、恒枝宏史
  • Journal Title: 有機合成化学協会誌 64 Pages: 49-60
  • NAID: 10016925229
  • Peer Reviewed
• [Journal Article] Chiral Synthesis of Poison-Frog Alkaloids 251N (2006)
  • Author(s): Toyooka, N.* ; Dejun, Z. ; Nemoto, H.* ; Garraffo, H.M. ; Spande, T.F. ; Daly, J.W.
  • Journal Title: and 221K Heterocycles 70 Pages: 541-548
  • Peer Reviewed
• [Journal Article] Enantioselective Syntheses of Poison-Frog Alkaloids : 219F and 221I and an Epimer of 193E (2006)
  • Author(s): Toyooka, N.* ; Dejun, Z. ; Nemoto, H.* ; Garraffo, H.M. ; Spande, T.F. ; Daly, J.W.
  • Journal Title: Tetrahedron Lett 47 Pages: 581-582
  • Peer Reviewed
• [Journal Article] The Enantioselective Synthesis of Poison-Frog Alkaloids(-)-203A, (-)-209B,(-)-231C, (-)-233D, and(-)-235B (2006)
  • Author(s): Toyooka, N.* ; Dejun, Z. ; Nemoto, H.* ; Garraffo, H.M. ; Spande, T.F. ; Daly, J.W.
  • Journal Title: Tetrahedron Lett 47 Pages: 577-580
  • Peer Reviewed
• [Journal Article] Chiral Synthesis of Poison-frog Alkaloids 251N and 221K (2006)
  • Author(s): Toyooka, N., Zhou, d., Nemoto, H., Garraffo, H.M., Spande, T.F., Daly, J.W.
  • Journal Title: Heterocycle 70 Pages: 541-8
  • NAID: 40015208578
• [Journal Article] 毒ガエルアルカロイドの合成とニコチン受容体に対する活性評価 (2006)
  • Author(s): 豊岡 尚樹, 根本 英雄, 恒枝 宏史
  • Journal Title: 有機合成化学協会誌 64 Pages: 49-60
  • NAID: 10016925229
• [Journal Article] The enantioselective synthesis of poison-frog alkaloids (-)-203A, (-)-209B, (-)-231C, (-)-233D, and (-)-235B" (2006)
  • Author(s): Toyooka, N., Dejun, Z., Nemoto, H., Garraffo, H.M., Spande, T.F., Daly, J.W.
  • Journal Title: Tetrahedron Lett. 47 Pages: 577-580
• [Journal Article] Enantioselective syntheses of poison-frog alkaloids : 219F and 221I and an epimer of 193E (2006)
  • Author(s): Toyooka, N., Dejun, Z., Nemoto, H., Garraffo, H.M., Spande, T.F., Daly, J.W.
  • Journal Title: Tetrahedron Lett. 47 Pages: 581-582
• [Presentation] Monomorine I 両対掌体の短工程合成 (2008)
  • Author(s): 周 徳軍, 豊岡尚樹, 根本英雄
  • Organizer: 日本薬学会北陸支部第118回例会
  • Place of Presentation: 富山
  • Year and Date: 2008-07-05
• [Presentation] アリから単離されたヒドロキシインドリチジンアルカロイドの合成 (2008)
  • Author(s): 豊岡尚樹, 周徳軍, 根本英雄, 山口薫, 恒枝宏史, 和田努, 笹岡利安, 手塚康弘, 門田重利, H. Martin Garraffo, Thomas F. Spande, John W. Daly
  • Organizer: 第38回複素環化学討論会
  • Place of Presentation: Fukuyama
• [Presentation] ピロリチジン型毒ガエルアルカロイドの合成研究 (2008)
  • Author(s): 周徳軍, 豊岡尚樹, 根本英雄, 手塚康弘, 門田重利, H. Martin Garraffo, Thomas F. Spande, John W. Daly
  • Organizer: 第34回反応と合成の進歩シンポジウム
  • Place of Presentation: Kyoto
• [Presentation] 毒ガエルアルカロイド179, 207Eの合成 (2008)
  • Author(s): 豊岡尚樹, 周徳軍, 古林創史, 恒枝宏史, 和田努, 酒井秀紀, 根本英雄, 笹岡利安, 手塚康弘, Subehan, 門田重利, H. Martin Garraffo, Thomas F. Spande, John W. Daly
  • Organizer: 日本薬学会第128年会
  • Place of Presentation: Yokohama
• [Presentation] ピロリチジン型毒ガエルアルカロイドの合成研究 (2008)
  • Author(s): 周 徳軍, 豊岡尚樹, 根本英雄, 山口 薫, 手塚康弘, 門田重利, Garraffo, H. M., Spande, T. F., Daly, J. W.
  • Organizer: 第34回反応と合成の進歩シンポジウム
  • Place of Presentation: 京都
• [Presentation] アリから単離されたヒドロキシインドリチジンアルカロイドの合成 (2008)
  • Author(s): 豊岡尚樹, 周 徳軍, 根本英雄, 山口 薫, 恒枝宏史, 和田 努, 笹岡利安, 手塚康弘, Garraffo, H. M., Spande, T. F., Daly, J. W., Jones, T. H.
  • Organizer: 第38回複素環化学討論会
  • Place of Presentation: 福山
• [Presentation] Synthesis of Proposed Structure of Poison-frog Alkaloids 207E and 179 and Their Inhibitory Effects on Nicotinic Acetylcholine Receptors (2007)
  • Author(s): Toyooka, N ; Zhou, D. ; Kobayashi, S. ; Tsuneki, H. ; Sasaoka, T. ; Nemoto, H. ; Garraffo, H. M. ; Spande, T. F. ; Daly, J. W.
  • Organizer: the 19th French-Japanese Symposium on Medicinal and Fine Chemistry
  • Place of Presentation: Toyama
• [Presentation] Synthesis of Proposed Structure of Poison-frog Alkaloids207E and 179 and Their Inhibitory Effects on Nicotinic Acetylcholine Receptors (2007)
  • Author(s): Naoki TOYOOKA, Dejun ZHOU, Soushi KOBAYASHI, Hiroshi TSUNEKI, Toshiyasu SASAOKA, Hideo NBMOTO, H. Martin GARRAFFO, Thomas F. SPANDE and John W. DALY
  • Organizer: The nineteenth French-Japanese Symposium on Medicinai and Fine Chemlstry (FJS 2007)
  • Place of Presentation: 富山
• [Presentation] Synthetic Studies on Biologically Active Alkaloids (2006)
  • Author(s): Toyooka, N.
  • Organizer: Xiamen University
  • Place of Presentation: Xiamen
• [Presentation] Synthetic Studies on Biologically Active Alkaloids (2006)
  • Author(s): Toyooka, N.
  • Organizer: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
  • Place of Presentation: Shanghai
• [Presentation] 毒ガエルアルカロイドの合成とそのニコチン受容体抑制活性評価 (2006)
  • Author(s): 周徳軍、豊岡尚樹、恒枝宏史、古林創史、笹岡利安、根本英雄、Daly, J.W. ; Spande, T.F. ; Garraffo, H.M.
  • Organizer: 第32回反応と合成の進歩シンポジウム
  • Place of Presentation: Hiroshima
• [Presentation] 毒ガエルアルカロイド233A, 251AA, 235Uのキラル合成 (2006)
  • Author(s): 周徳軍、豊岡尚樹、根本英雄、Garraffo, H.M. ; Spande, T.F. ; Daly, J.W.
  • Organizer: 日本薬学会北陸支部第114例会
  • Place of Presentation: Kanazawa
• [Presentation] Chiral Synthesis of 5, 8-Disubstituted Indolizidine Type Poison-frog Alkaloids (2006)
  • Author(s): Toyooka, N. ; Zhou, D. ; Nemoto, H. ; Garraffo, H.M. ; Spande, T.F. ; Daly, J W.
  • Organizer: International Molecular Chirality Conference in Toyama
  • Place of Presentation: Toyama
• [Remarks]
  • URL: http://www.pha.u-toyama.ac.jp/mediche2/index-j.html