| Autor: |
Mitronova GY; Department of NanoBiophotonics, Max Planck Institute for Multidisciplinary Sciences, Am Fassberg 11, Göttingen 37077, Germany.; German Centre for Cardiovascular Research (DZHK), Partner Site Göttingen, Göttingen 37075, Germany., Quentin C; Department of NanoBiophotonics, Max Planck Institute for Multidisciplinary Sciences, Am Fassberg 11, Göttingen 37077, Germany., Belov VN; Department of NanoBiophotonics, Max Planck Institute for Multidisciplinary Sciences, Am Fassberg 11, Göttingen 37077, Germany., Wegener JW; Department of Cardiology & Pulmonology, Heart Research Center Göttingen, University Medical Center Göttingen, Robert-Koch-Strasse 42a, Göttingen 37075, Germany.; German Centre for Cardiovascular Research (DZHK), Partner Site Göttingen, Göttingen 37075, Germany., Kiszka KA; Department of NanoBiophotonics, Max Planck Institute for Multidisciplinary Sciences, Am Fassberg 11, Göttingen 37077, Germany., Lehnart SE; Department of Cardiology & Pulmonology, Heart Research Center Göttingen, University Medical Center Göttingen, Robert-Koch-Strasse 42a, Göttingen 37075, Germany.; German Centre for Cardiovascular Research (DZHK), Partner Site Göttingen, Göttingen 37075, Germany. |
| Abstrakt: |
To discover new multifunctional agents for the treatment of cardiovascular diseases, we designed and synthesized a series of compounds with a cyclopropyl alcohol moiety and evaluated them in biochemical assays. Biological screening identified derivatives with dual activity: preventing Ca 2+ leak through ryanodine receptor 2 (RyR2) and enhancing cardiac sarco-endoplasmic reticulum (SR) Ca 2+ load by activation of Ca 2+ -dependent ATPase 2a (SERCA2a). The compounds that stabilize RyR2 at micro- and nanomolar concentrations are either structurally related to RyR-stabilizing drugs or Rycals or have structures similar to them. The novel compounds also demonstrate a good ability to increase ATP hydrolysis mediated by SERCA2a activity in cardiac microsomes, e.g., the half-maximal effective concentration (EC 50 ) was as low as 383 nM for compound 12a, which is 1,4-benzothiazepine with two cyclopropanol groups. Our findings indicate that these derivatives can be considered as new lead compounds to improve cardiac function in heart failure. |
