"Dual Anta-Inhibitors" of the A_2A Adenosine Receptor and Casein Kinase CK1delta: Synthesis, Biological Evaluation, and Molecular Modeling Studies

• Main Authors: Andrea Spinaci (Author), Michela Buccioni (Author), Daniela Catarzi (Author), Chang Cui (Author), Vittoria Colotta (Author), Diego Dal Ben (Author), Eleonora Cescon (Author), Beatrice Francucci (Author), Ilenia Grieco (Author), Catia Lambertucci (Author), Gabriella Marucci (Author), Davide Bassani (Author), Matteo Pavan (Author), Flavia Varano (Author), Stephanie Federico (Author), Giampiero Spalluto (Author), Stefano Moro (Author), Rosaria Volpini (Author)
• Format: Book
• Published: MDPI AG, 2023-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Based on a screening of a chemical library of A_2A adenosine receptor (AR) antagonists, a series of di- and tri-substituted adenine derivatives were synthesized and tested for their ability to inhibit the activity of the enzyme casein kinase 1 delta (CK1δ) and to bind adenosine receptors (ARs). Some derivatives, here called "dual anta-inhibitors", demonstrated good CK1δ inhibitory activity combined with a high binding affinity, especially for the A_2AAR. The <i>N</i>⁶-methyl-(2-benzimidazolyl)-2-dimethyamino-9-cyclopentyladenine (<b>17</b>, IC₅₀ = 0.59 μM and KiA_2A = 0.076 μM) showed the best balance of A_2AAR affinity and CK1δ inhibitory activity. Computational studies were performed to simulate, at the molecular level, the protein-ligand interactions involving the compounds of our series. Hence, the dual anta-inhibitor <b>17</b> could be considered the lead compound of new therapeutic agents endowed with synergistic effects for the treatment of chronic neurodegenerative and cancer diseases.

Item Description

10.3390/ph16020167
1424-8247