Polypharmacology of <i>N</i><sup>6</sup>‑(3-Iodobenzyl)­adenosine-5′‑<i>N</i>‑methyluronamide (IB-MECA) and Related A<sub>3</sub> Adenosine Receptor Ligands: Peroxisome Proliferator Activated Receptor (PPAR) γ Partial Agonist and PPARδ Antagonist Activity Suggests Their Antidiabetic Potential

A<sub>3</sub> adenosine receptor (AR) ligands including A<sub>3</sub> AR agonist, <i>N</i><sup>6</sup>-(3-iodobenzyl)­adenosine-5′-<i>N</i>-methyl­uronamide (<b>1a</b>, IB-MECA) were examined for adiponectin production in human bone marrow mesenchymal stem cells (hBM-MSCs). In this model, <b>1a</b> significantly increased adiponectin production, which is associated with improved insulin sensitivity. However, A<sub>3</sub> AR antagonists also promoted adiponectin production in hBM-MSCs, indicating that the A<sub>3</sub> 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, <b>1a</b> and its structural analogues A<sub>3</sub> 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.