Development of new analgesics based on spinal cord Cyr61-integrin binding inhibition

• Project/Area Number: 18K07365
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: University of Toyama
• Principal Investigator: Takasaki Ichiro 富山大学, 学術研究部工学系, 准教授 (00397176)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: Cyr61 / 機械的アロディニア / インテグリン / 小分子拮抗薬 / ケモカイン / 小分子阻害薬 / アストロサイト / 疼痛 / 創薬

Outline of Final Research Achievements

Cyr61 induces pain by binding to β1 integrin. In this study, we aimed to develop an integrin β1 small molecule antagonist. Ten candidate compounds were selected by in silico screening using the Cry61-integrin β1 binding model, and one compound (F) was obtained by in vitro inhibitory activity. However, Compound F did not show a strong analgesic effect. Therefore, we designed a chimeric compound of an existing peptide antagonist and compound F, and succeeded in obtaining compound K, which has a strong inhibitory activity. Compound K exhibited an analgesic effect superior to that of compound F. In the future, we plan to work on the synthesis of derivative compounds of compound K with the aim of acquiring compounds with more potent analgesic effects.

Academic Significance and Societal Importance of the Research Achievements

Cyr61の痛み慢性化への関与に関する研究は，国内外において我々の研究グループしか行っておらず独自性・新規性は非常に高い。新規鎮痛薬の開発においてターゲット分子の探索研究に限界が生じている現状において，われわれが着目しているCyr61-β1インテグリン系を標的とした創薬は，新薬開発に大きな風穴を開けることができると考えている。本研究において，新規インテグリン阻害化合物の獲得に成功した。引き続き本研究を遂行し成し遂げることで，超高齢化社会の到来と共に，今後本邦で大きく増大することが予想される慢性疼痛患者の福祉に大きく貢献できると考えている。

Research Products

• [Journal Article] TBX5 R264K acts as a modifier to develop dilated cardiomyopathy in mice independently of T-box pathway (2020)
  • Author(s): Miyao N., Hata Y., Izumi H., Nagaoka R., Oku Y., Takasaki I., Ishikawa T., Takarada S., Okabe M., Nakaoka H., Ibuki K., Ozawa S., Yoshida T., Hasegawa H., Makita N., Nishida N., Mori H., Ichida F., Hirono K.
  • Journal Title: PLOS ONE Volume: 15 Issue: 4 Pages: 0227393-0227393
  • DOI: 10.1371/journal.pone.0227393
  • Peer Reviewed / Open Access
• [Journal Article] Differential localization and roles of splice variants of rat suppressor of cancer cell invasion (SCAI) in neuronal cells. (2020)
  • Author(s): Mizukoshi M, Nozawa A, Oomizo S, Ihara D, Shiota J, Kikuchi K, Kaito M, Ishibashi Y, Ishikawa M, Fukuchi M, Tsuda M, Takasaki I, Tabuchi A.
  • Journal Title: Biochem Biophys Res Commun Volume: 529(3) Issue: 4 Pages: 615-621
  • DOI: 10.1111/jnc.15122
  • Peer Reviewed / Open Access
• [Journal Article] Attenuation of relaxing response induced by pituitary adenylate cyclase-activating polypeptide in bronchial smooth muscle of experimental asthma. (2020)
  • Author(s): Chiba Y, Ueda C, Kohno N, Yamashita M, Miyakawa Y, Ando Y, Suto W, Hirabayashi T, Takenoya F, Takasaki I, Kamei J, Sakai H, Shioda S.
  • Journal Title: Am J Physiol Lung Cell Mol Physiol. Volume: 319 Issue: 5 Pages: L786-L793
  • DOI: 10.1152/ajplung.00315.2020
  • Peer Reviewed / Open Access
• [Journal Article] Synthesis of a novel and potent small-molecule antagonist of PAC1 receptor for the treatment of neuropathic pain. (2019)
  • Author(s): Takasaki I, Ogashi H, Okada T, Shimodaira A, Hayakawa D, Watanabe A, Miyata A, Kurihara T, Gouda H, Toyooka N.
  • Journal Title: Eur J Med Chem. Volume: 186 Pages: 111902-111902
  • DOI: 10.1016/j.ejmech.2019.111902
  • Peer Reviewed / Open Access
• [Journal Article] Bidirectional Crosstalk Between Neutrophils and Adipocytes Promotes Adipose Tissue Inflammation (2019)
  • Author(s): Watanabe Y, Nagai Y, Honda H, Okamoto N, Yanagibashi T, Ogasawara M, Yamamoto S, Imamura R, Takasaki I, Hara H, Sasahara M, Arita M, Hida S, Taniguchi S, Suda T, Takatsu K.
  • Journal Title: FASEB J. Volume: 33(11) Issue: 11 Pages: 11821-11835
  • DOI: 10.1096/fj.201900477rr
  • Peer Reviewed / Open Access
• [Journal Article] Screening inducers of neuronal BDNF gene transcription using primary cortical cell cultures from BDNF-luciferase transgenic mice (2019)
  • Author(s): Fukuchi Mamoru、Okuno Yui、Nakayama Hironori、Nakano Aoi、Mori Hisashi、Mitazaki Satoru、Nakano Yuka、Toume Kazufumi、Jo Michiko、Takasaki Ichiro、Watanabe Kazuki、Shibahara Naotoshi、Komatsu Katsuko、Tabuchi Akiko、Tsuda Masaaki
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 11833-11833
  • DOI: 10.1038/s41598-019-48361-4
  • Peer Reviewed / Open Access
• [Journal Article] The novel small-molecule antagonist of PAC1 receptor attenuates formalin-induced inflammatory pain behaviors in mice (2019)
  • Author(s): Takasaki Ichiro、Nakamura Koji、Shimodaira Ayaka、Watanabe Ai、Du Nguyen Huy、Okada Takuya、Toyooka Naoki、Miyata Atsuro、Kurihara Takashi
  • Journal Title: Journal of Pharmacological Sciences Volume: 139 Issue: 2 Pages: 129-132
  • DOI: 10.1016/j.jphs.2018.11.011
  • Peer Reviewed / Open Access
• [Journal Article] In silico screening identified novel small-molecule antagonists of PAC1 receptor. (2018)
  • Author(s): Takasaki I, Watanabe A, Yokai M, Watanabe Y, Hayakawa, D, Nagashima, R, Fukuchi, M, Okada, T, Toyooka, N, Miyata, A, Gouda H, Kurihara T.
  • Journal Title: J. Pharmacol. Exp. Ther. Volume: - Issue: 1 Pages: 1-8
  • DOI: 10.1124/jpet.117.245415
  • Peer Reviewed / Open Access
• [Presentation] Possible involvement of PACAP-PAC1 receptor signaling system to itch sensation in mice. (2021)
  • Author(s): 髙﨑一朗，加藤翔，池田竜太，村田万祐子，斎藤弘樹，神戸悠輝，合田浩明，岡田卓哉，豊岡尚樹，宮田篤郎，栗原崇
  • Organizer: 第94回日本薬理学会年会
• [Presentation] PAC1受容体小分子アンタゴニストのニトログリセリン誘発性片頭痛関連行動に対する効果 (2020)
  • Author(s): 岡田健斗，柴崎知華，宮田篤郎，栗原崇，髙﨑一朗
  • Organizer: 第71回日本薬理学会北部会
• [Presentation] 新規PAC1受容体アンタゴニストはアストロサイト活性を阻害することで，パクリタキセル誘発性機械的アロディニアを減弱する (2020)
  • Author(s): 井上新大，岡田卓哉，豊岡尚樹，宮田篤郎，栗原崇，髙﨑一朗
  • Organizer: 第71回日本薬理学会北部会
• [Presentation] そう痒における新規PACAP type 1受容体小分子拮抗薬の効果 (2020)
  • Author(s): 髙﨑一朗，池田竜太，村田万祐子，加藤翔，岡田卓哉，豊岡尚樹，合田浩明，宮田篤郎，栗原崇
  • Organizer: 第93回日本薬理学会年会
• [Presentation] PACAP誘発嫌悪行動は一種の掻痒反応を表しているのか？ー脊髄痒み伝達におけるPACAP情報伝達系の関与の可能性ー (2020)
  • Author(s): 栗原崇，池田竜太，斎藤弘樹，村田万祐子，神戸悠輝，加藤翔，岡田卓哉，豊岡尚樹，合田浩明，宮田篤郎，髙﨑一朗
  • Organizer: 第93回日本薬理学会年会
• [Presentation] 新規PAC1受容体小分子アンタゴニストはニトログリセリン誘発性頭痛関連行動を抑制する (2020)
  • Author(s): 岡田健斗，岡田卓哉，豊岡尚樹，合田浩明，宮田篤郎，栗原崇，髙﨑一朗
  • Organizer: 第93回日本薬理学会年会
• [Presentation] 新規PAC1受容体アンタゴニストは脊髄アストロサイトの活性抑制を介してパクリタキセル誘発機械的アロディニアを減弱する (2020)
  • Author(s): 井上新大，岡田卓哉，豊岡尚樹，合田浩明，宮田篤郎，栗原崇，髙﨑一朗
  • Organizer: 第93回日本薬理学会年会
• [Presentation] 新規PAC1受容体小分子アンタゴニストの合成と神経障害性疼痛モデルマウスを用いた薬効評価 (2019)
  • Author(s): 下平文香，大樫知奈，渡辺藍，岡田卓哉，豊岡尚樹，合田浩明，宮田篤郎，栗原崇，髙﨑一朗
  • Organizer: 第15回GPCR研究会
• [Presentation] PACAP/PAC1受容体シグナリングはオキサリプラチン誘発急性末梢神経障害疼痛発症に関与するか？ (2019)
  • Author(s): 栗原崇，上田隆拡，長島涼太，斎藤弘樹，豊岡尚樹，合田浩明，宮田篤郎，髙﨑一朗
  • Organizer: 第41回日本疼痛学会
• [Presentation] ニトログリセリン誘発片頭痛モデルマウスの疼痛関連行動におよぼす新規PAC1受容体アンタゴニストの効果 (2019)
  • Author(s): 髙﨑一朗，岡田健斗，柴崎知華，下平文香，岡田卓哉，豊岡尚樹，合田浩明，宮田篤郎，栗原崇
  • Organizer: 第41回日本疼痛学会
• [Presentation] Novel small-molecule PAC1 receptor antagonist inhibits nitroglycerin-induced migraine-related behabiors in mice. (2019)
  • Author(s): Takasaki I, Okada K, Shibasaki C, Shimodaira A, Okada T, Toyooka N, Gouda H, Miyata A, Kurihara T.
  • Organizer: Akira Arimura Memorial VIP/PACAP and Related Peptides Symposium
  • Int'l Joint Research
• [Presentation] Novel PAC1 receptor antagonist ameliorates neuropathic pain and associated anxiety-like behavior in mice. (2019)
  • Author(s): Shimodaira A, Watanabe A, Toyooka N, Okada T, Gouda H, Miyata A, Kurihara T, Takasaki I.
  • Organizer: Akira Arimura Memorial VIP/PACAP and Related Peptides Symposium
  • Int'l Joint Research
• [Presentation] Possible involvement of PACAP signaling in chronic pain-induced negative emotional responses in mice. (2019)
  • Author(s): Kurihara T, Hashiguchi K, Shimodaira A, Nguyen TT, Kambe Y, Takasaki I, Miyata A
  • Organizer: Akira Arimura Memorial VIP/PACAP and Related Peptides Symposium
  • Int'l Joint Research
• [Presentation] PAC1受容体低分子拮抗薬のイン・シリコ創薬～難治性慢性疼痛治療に向けて～ (2019)
  • Author(s): 髙﨑一朗
  • Organizer: 第11回トランスポーター研究会九州部会
  • Invited
• [Presentation] PACAP情報伝達系は慢性疼痛に伴う負情動行動発現に関与するか？ (2019)
  • Author(s): 橋口浩平，下平文香，Thanh Trung Nguyen，神戸悠輝，杉村光隆，髙﨑一朗，栗原崇，宮田篤郎
  • Organizer: 第11回トランスポーター研究会九州部会
• [Presentation] PACAP/PAC1受容体シグナリングはオキサリプラチン誘発急性末梢神経障害性疼痛発症に関与するか？ (2019)
  • Author(s): 斎藤弘樹，上田隆拡，長島涼太，豊岡尚樹，合田浩明，宮田篤郎，髙﨑一朗，栗原崇
  • Organizer: 第11回トランスポーター研究会九州部会
• [Presentation] マウスを用いた疼痛研究と創薬 (2019)
  • Author(s): 髙﨑一朗
  • Organizer: 第1回感覚研究シンポジウム
• [Presentation] 慢性疼痛発症メカニズムにおけるPACAP誘発脊髄アストロサイト・ニューロン乳酸シャトル活性化の関与 (2019)
  • Author(s): 栗原崇，神戸悠輝，用皆正文，下平文香，髙﨑一朗，宮田篤郎
  • Organizer: 第92回日本薬理学会年会
  • Invited
• [Presentation] 難治性疼痛治療を目指した新規PAC1受容体小分子アンタゴニストの創薬 (2019)
  • Author(s): 髙﨑一朗，豊岡尚樹，宮田篤郎，合田浩明，栗原崇
  • Organizer: 日本薬学会第139年会
  • Invited
• [Presentation] PACAP-induced pain responses are mediated by spinal Cyr61-chemokine signaling pathway. (2018)
  • Author(s): Ogata T, Maeda T, Yokai M, Miyata A, Kurihara T, Takasaki I
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] Novel PAC1 receptor antagnist inhibits nitroglycerin-induced migraine -like pain responses in mice. (2018)
  • Author(s): Shimodaira A, Shibasaki C, Watanabe A, Toyooka N, Okada T, Miyata A, Kurihara T, Takasaki I
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] Pharmacological evaluation of novel PAC1 receptor antagnist on oxaliplatin-induced cold allodynia in mice. (2018)
  • Author(s): Ueda T, Nagashima R, Watanabe A, Okada T, Toyooka N, Miyata A, Kurihara T, Takasaki I
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] Discovery of small-molecule antagonists of PAC1 receptor for the treatment of neuropathic pain. (2018)
  • Author(s): Takasaki I
  • Organizer: 22nd International Symposium on Regulatory Peptides
  • Int'l Joint Research / Invited
• [Remarks] 生体情報薬理学研究室ホームページ
  • URL: http://www3.u-toyama.ac.jp/yakuri/index.html