A3 adenosine receptor (AR) ligands including A3 AR agonist, N6-(3-iodobenzyl)adenosine-5′-N-methyluronamide (1a, IB-MECA) were examined for adiponectin production in human bone marrow mesenchymal stem cells (hBM-MSCs). In this model, 1a significantly increased adiponectin production, which is associated with improved insulin sensitivity. However, A3 AR antagonists also promoted adiponectin production in hBM-MSCs, indicating that the A3 AR pathway may not be directly involved in the adiponectin promoting activity. In a target deconvolution study, their adiponectin-promoting activity was significantly correlated to their binding activity to both peroxisome proliferator activated receptor (PPAR) γ and PPARδ. They functioned as both PPARγ partial agonists and PPARδ antagonists. In the diabetic mouse model, 1a and its structural analogues A3 AR antagonists significantly decreased the serum levels of glucose and triglyceride, supporting their antidiabetic potential. These findings indicate that the polypharmacophore of these compounds may provide therapeutic insight into their multipotent efficacy against various human diseases.
Bibliographical noteFunding Information:
This study was partly supported by National Research Foundation of Korea (NRF) grants funded by the Ministry of Science, ICT, and Future Planning (Grants 2014M3C9A-2064603, 2015R1A2A2A01008408, and 370C-20160046), by NIDDK Intramural Research Program (Grant ZIA DK031117), and by Promising-Pioneering Researcher Program through the Seoul National University (SNU) in 2015.
© 2017 American Chemical Society.