|
|||||
|
|
Development of novel adenosine receptor ligands based on the 3-amidocoumarin scaffold |
|
| Affiliation: | 1. CIQUP, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal;2. Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain;3. Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032, USA;4. Institut für Pharmakologie und Toxikologie, Universität Würzburg, 97078 Würzburg, Germany;1. Área Académica de Química, Universidad Autónoma del Estado de Hidalgo, km 4.5 Carretera Pachuca-Tulancingo, Mineral de la Reforma, Hidalgo 42184, Mexico;2. Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Apartado 137, Morelia, Michoacán 58000, Mexico;3. Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado 14-740, México D.F. 07000, Mexico;1. Laser & Plasma Technology Division, Bhabha Atomic Research Centre, Mumbai 400085 , India;2. Department of Physics, Savitribai Phule Pune University, Pune 411007, India;1. Ningbo University of Technology, No. 55-155 Cui Bai Road, Ningbo 315016, China;2. V. Lashkaryov Institute of Semiconductor Physics NAS of Ukraine, 41 Nauky Pr., 03028 Kyiv, Ukraine;1. Departamento de Química Inorgánica, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Santiago 22, Chile;2. Departamento de Farmacia, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Santiago 22, Chile |
| Abstract: |  With the aim of finding new adenosine receptor (AR) ligands presenting the 3-amidocoumarin scaffold, a study focusing on the discovery of new chemical entities was carried out. The synthesized compounds 1–8 were evaluated in radioligand binding (A1, A2A and A3) and adenylyl cyclase activity (A2B) assays in order to determine their affinity for human AR subtypes. The 3-benzamide derivative 4 showed the highest affinity of the whole series and was more than 30-fold selective for the A3 AR (Ki = 3.24 μM). The current study supported that small structural changes in this scaffold allowed modulating the affinity resulting in novel promising classes of A1, A2A, and/or A3 AR ligands. We also performed docking calculations in hA2A and hA3 to identify the hypothetical binding mode for the most active compounds. In addition, some ADME properties were calculated in order to better understand the potential of these compounds as drug candidates. |
| Keywords: | 3-Amidocoumarins Adenosine ligands Theoretical ADME properties Molecular modeling calculations |
| 本文献已被 ScienceDirect 等数据库收录！ | |