Development of non-peptide type of angiotensin II type 1 receptor ligand as a biased agonist

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08593
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Fukuoka University
• Principal Investigator: Miura Shinichiro 福岡大学, 医学部, 教授 (20343709)
• Co-Investigator(Kenkyū-buntansha): 末松 保憲 福岡大学, 医学部, 講師 (70716927)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: アンジオテンシンII / Biased ligands / 非ペプチド型 / 細胞内シグナル

Outline of Final Research Achievements

We synthesized three non-peptide type of AT1 receptor ligands (Compound A, B and C) as candidates of biased ligands. Inositol phosphate (IP) production and extracellular signal-regulated kinase (ERK) 1/2 activation were measured and examined binding modes of receptor-ligand by competition binding study, and subsequently analyzed whether these ligands would induce IP production and ERK1/2 activation.Compound B and C decreased and increased IP production, respectively, whereas Compound A did not change IP production. Compound B and C, but not Compound A, activated ERK1/2. L112A had a key role of IP production.In conclusions, compound A, B and C were a neutral antagonist, an inverse agonist, and an agonist with regard to IP production, respectively. On the other hand, Compound B and C, but not Compound A, were agonists to ERK1/2 activation. Thus, we developed non-peptide type of AT1 receptor compound as a biased ligand.

Free Research Field

循環器病学

Academic Significance and Societal Importance of the Research Achievements

AT1受容体は、心血管系疾患の発症・進展に強く関わっており、Biased ligandsの概念を基に心不全治療薬を開発する。AT1受容体をターゲットとした適切な急性心不全治療薬は、Gタンパク質共役経路は阻害し、βアレスチン経路を作動するAT1受容体選択的作動薬の開発である。以上より、私たちは、非ペプチド型AT1受容体選択的作動薬(Biased ligands)をデザイン・合成する。新規化合物がどの細胞内シグナルを伝達しているかを確認し、心不全に効果的なシグナルを選択的に伝達しているかを検討する。