Discovery of muscarinic acetylcholine receptor partial agonists

• Project/Area Number: 15K18903
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: Kansai University
• Principal Investigator: Sumiyoshi Takaaki 関西大学, 化学生命工学部, 准教授 (50738911)
• Research Collaborator: NAKAMURA Arisa ; NAMBARA Takuya ; MURAKAMI Masato
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: ムスカリン受容体作動薬 / 部分作動薬 / 創薬化学 / 光学活性体 / 構造活性相関 / Gタンパク結合型受容体 / 有機合成化学 / 中枢神経作用薬

Outline of Final Research Achievements

Muscarinic acetylcholine receptors (M1-M5) are potent drug targets for the treatment of various central nerve system diseases. Among the subtypes, activation of M1 receptor leads to improvement of cognitive impairment. Although many medicinal chemists have challenged to discover selective M1 agonists, most of the compounds did not show enough high subtype-selectivity to dissociate the side effects.
In this study, we synthesized benzimidazolone derivatives and identified subtype selective M1 receptor partial agonists based on the structure-activity relationship information. The identified compounds are potent for the treatment central nerve system diseases.

Research Products

• [Journal Article] Discovery of new low-molecular-weight p53-Mdmx disruptors and their anti-cancer activities (2016)
  • Author(s): Uesato, S.; Matsuura, Y.; Matsue, S.; Sumiyoshi, T.; Hirata, Y.; Takemoto, S.; Kawaratani, Y.; Yamai, Y.; Ishida, K.; Sasaki, T.; Enari, M.
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 24 Issue: 8 Pages: 1919-1926
  • DOI: 10.1016/j.bmc.2016.03.021
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Discovery of dihydroquinazolinone derivatives as potent, selective, and CNS-penetrant M1 and M4 muscrinic acetylcholine receptors agonists (2015)
  • Author(s): Uruno, Y.; Konishi, Y.; Suwa, A.; Takai, K.; Tojo, K.; Nakako, T.; Sakai, M.; Enomoto, T.; Matsuda, H.; Kitamura, A.; Sumiyoshi, T.
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 25 Issue: 22 Pages: 5357-5361
  • DOI: 10.1016/j.bmcl.2015.09.032
  • Peer Reviewed
• [Journal Article] Cyclic Model for the Asymmetric Conjugate Addition of Organolithiums with Enoates (2015)
  • Author(s): Yasutomo Yamamoto
  • Journal Title: Synthesis Volume: 47 Issue: 15 Pages: 2256-2264
  • DOI: 10.1055/s-0034-1380702
  • NAID: 120005674638
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A Short Synthesis of (+)-β-Lycorane by Asymmetric Conjugate Addition Cascade. (2015)
  • Author(s): Ｋｉｙｏｓｈｉ Ｔｏｍｉｏｋａ
  • Journal Title: Ｔｅｔｒａｈｅｄｒｏｎ Volume: 71 Issue: 39 Pages: 7222-7226
  • DOI: 10.1016/j.tet.2015.03.014
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] HDAC6選択的阻害活性を有するベンズアミド誘導体の探索研究 (2017)
  • Author(s): 平中誠弥、上里新一、伊藤昭博、吉田稔、長岡康夫、住吉孝明
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台国際センター・東北大学
  • Year and Date: 2017-03-24
• [Presentation] ヒストン脱アセチル化酵素（HDAC）阻害剤亜鉛結合部位の構造活性相関によるHDAC6選択的阻害剤の創製 (2017)
  • Author(s): 平中誠弥、上里新一、長岡康夫、伊藤昭博、吉田 稔、住吉孝明
  • Organizer: 第21回関西大学先端科学技術シンポジウム
  • Place of Presentation: 関西大学
  • Year and Date: 2017-01-19
• [Presentation] 脳移行性を有するヒストン脱アセチル化酵素（HDAC）阻害剤の探索研究 (2016)
  • Author(s): 平中誠弥、上里新一、長岡康夫、伊藤昭博、吉田 稔、平田佳之、住吉孝明
  • Organizer: 第66回日本薬学会近畿支部総会・大会
  • Place of Presentation: 大阪薬科大学
  • Year and Date: 2016-10-15
• [Presentation] 不斉非対称化反応を用いた光学活性3,3-ジ置換オキシインドールの合成研究 (2016)
  • Author(s): 石田恭次、山井悠介、上里新一、長岡康夫、住吉孝明
  • Organizer: 第66回日本薬学会近畿支部総会・大会
  • Place of Presentation: 大阪薬科大学
  • Year and Date: 2016-10-15
• [Presentation] Synthesis and biological evaluation of CNS-penetrant histone deacetylase inhibitor. (2016)
  • Author(s): S. Hiranaka, Y. Nagaoka, S. Uesato, A. Ito, M. Yoshida, T. Sumiyoshi
  • Organizer: The 11th International Symposium in Science and Technology at Kansai University 2016
  • Place of Presentation: Kansai University
  • Year and Date: 2016-07-26
• [Presentation] Intramolecular macrocyclic cyclization by photo-affinity reaction. (2016)
  • Author(s): R. Iiji, Y. Nagaoka, T. Sumiyoshi
  • Organizer: The 11th International Symposium in Science and Technology at Kansai University 2016
  • Place of Presentation: Kansai University
  • Year and Date: 2016-07-26
• [Presentation] Asymmetric synthesis of 3,3-disubstituted oxindoles using chiral acids. (2016)
  • Author(s): M. Shimizu, Y. Yamai, K. Ishida, Y. Nagaoka, T. Sumiyoshi.
  • Organizer: The 11th International Symposium in Science and Technology at Kansai University 2016
  • Place of Presentation: Kansai University
  • Year and Date: 2016-07-26
• [Presentation] Efficient synthesis of (±)-coerulescine. (2016)
  • Author(s): K. Takeuchi, K. Ishida, Y. Yamai, Y. Nagaoka, T. Sumiyoshi
  • Organizer: The 11th International Symposium in Science and Technology at Kansai University 2016
  • Place of Presentation: Kansai University
  • Year and Date: 2016-07-26
• [Presentation] Concise synthesis of spiro-fused oxindole derivatives. (2016)
  • Author(s): I. Natsutani, R. Iwata, Y. Yamai, K. Ishida, Y. Nagaoka, T. Sumiyoshi
  • Organizer: The 11th International Symposium in Science and Technology at Kansai University 2016
  • Place of Presentation: Kansai University
  • Year and Date: 2016-07-26
• [Presentation] Synthesis and biological evaluation of benzamide derivatives as anti-cancer prodrugs. (2016)
  • Author(s): R. Inoue, S. Takemoto, Y. Nakatsuji, Y. Nagaoka, S. Uesato, S. Oishi, M. Enari, T. Sumiyoshi
  • Organizer: The 11th International Symposium in Science and Technology at Kansai University 2016
  • Place of Presentation: Kansai University
  • Year and Date: 2016-07-26
• [Presentation] Synthesis and biological evaluation of catechin derivatives. (2016)
  • Author(s): K. Kawaguchi, S. Uesato, Y. Nagaoka, S. Yamasaki, T. Sumiyoshi
  • Organizer: The 11th International Symposium in Science and Technology at Kansai University 2016
  • Place of Presentation: Kansai University
  • Year and Date: 2016-07-26
• [Presentation] p53活性化作用を有する2-aminobenzenethiol誘導体の探索研究 (2016)
  • Author(s): 竹本涼穂，松浦佳宏，井上涼佑，江成政人，大石真也，藤井信孝，長岡康夫，上里新一，住吉孝明
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: パシフィコ横浜（神奈川）
  • Year and Date: 2016-03-27
• [Presentation] ジケトピペラジン構造を有するヒストン脱アセチル化酵素阻害剤の探索研究 (2016)
  • Author(s): 布袋彩菜，平田佳之，上里新一，長岡康夫，住吉孝明
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: パシフィコ横浜（神奈川）
  • Year and Date: 2016-03-27
• [Presentation] カルボニル基活性化を基盤とする置換oxindole化合物の簡便合成 (2015)
  • Author(s): 山井悠介，石田恭次，周琳濤，竹内一喜，清水雅明，長岡康夫，住吉孝明
  • Organizer: 第41回反応と合成の進歩シンポジウム
  • Place of Presentation: 近畿大学（大阪）
  • Year and Date: 2015-10-26
• [Presentation] 不斉非対称化反応を基盤とする3,3-disubstituted oxindole の合成研究 (2015)
  • Author(s): 石田恭次，山井悠介，上里新一，長岡康夫，住吉孝明
  • Organizer: 第65回日本薬学会近畿支部総会・大会
  • Place of Presentation: 大阪大谷大学（大阪）
  • Year and Date: 2015-10-17
• [Presentation] オキシインドール環化反応の反応機構解明 (2015)
  • Author(s): 山井悠介，石田恭次，竹内一喜，清水雅明，上里新一，長岡康夫，住吉孝明
  • Organizer: 第65回日本薬学会近畿支部総会・大会
  • Place of Presentation: 大阪大谷大学（大阪）
  • Year and Date: 2015-10-17
• [Presentation] Selective synthesis of 3,3-disubstituted oxindole and N-hydroxy oxindole via activation of carbonyl group by acid (2015)
  • Author(s): Sumiyoshi, T.; Yamai, Y.; Ishida, K.; Shimizu, M.; Zhu, L.; Takeuchi, K.; Uesato, S.; Nagaoka, Y.
  • Organizer: The 10th International Symposium in Science and Technology 2015
  • Place of Presentation: Chulalongkorn University, Bangkok, Thailand
  • Year and Date: 2015-08-31
  • Int'l Joint Research
• [Presentation] Intramolecular macrocyclic cyclization by photo-affinity reaction of benzophenone with alcohol (2015)
  • Author(s): Iiji, R.; Ishida, K.; Nagaoka, Y.; Sumiyoshi, T.
  • Organizer: The 10th International Symposium in Science and Technology 2015
  • Place of Presentation: Chulalongkorn University, Bangkok, Thailand
  • Year and Date: 2015-08-31
  • Int'l Joint Research
• [Presentation] Synthesis and biological evaluation of hybrid compounds of histone deacetylase inhibitor and histamine receptor blocker (2015)
  • Author(s): Hiranaka, S.; Hotei, A.; Nagaoka, Y.; Sumiyoshi, T.
  • Organizer: The 10th International Symposium in Science and Technology 2015
  • Place of Presentation: Chulalongkorn University, Bangkok, Thailand
  • Year and Date: 2015-08-31
  • Int'l Joint Research
• [Presentation] Synthesis and biological evaluation of benzamide derivatives as p53-Mdmx interaction inhibitors (2015)
  • Author(s): Inoue, R.; Takemoto, S.; Oishi, S.; Enari, M.; Uesato, S.; Nagaoka, Y.; Sumiyoshi, T.
  • Organizer: The 10th International Symposium in Science and Technology 2015
  • Place of Presentation: Chulalongkorn University, Bangkok, Thailand
  • Year and Date: 2015-08-31
  • Int'l Joint Research
• [Presentation] 化学者からみた次世代創薬の動向と薬物動態研究者への期待 (2015)
  • Author(s): 住吉孝明
  • Organizer: 第 29回日本薬物動態学会ワークショップ
  • Place of Presentation: 学術総合センター（東京）
  • Year and Date: 2015-05-14
  • Invited