Polypharmacology of N⁶-(3-Iodobenzyl)adenosine-5′-N-methyluronamide (IB-MECA) and Related A₃ Adenosine Receptor Ligands: Peroxisome Proliferator Activated Receptor (PPAR) γ Partial Agonist and PPARδ Antagonist Activity Suggests Their Antidiabetic Potential

Abstract

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.

Biotransformation of polyunsaturated fatty acids to bioactive hepoxilins and trioxilins by microbial enzymes

“…The high micromolar concentration of HETE, HX or TrXs up to 20 μM was used to determine the transcriptional activity of PPARγ because there was no cytotoxicity at this concentration. The concentration up to 20−40 μM has been used for PPARγ partial agonists due to their weak activity and no cytotoxicity 59 – 61 . The concentration of the full agonist TRO was the same as those used in other reports 47 , 62 .…”

LJ-1888, a selective antagonist for the A3 adenosine receptor, ameliorates the development of atherosclerosis and hypercholesterolemia in apolipoprotein E knock-out mice

“…Recently, Yu et al . presented the poly-pharmacological effects of A 3 AR agonist (IB-MECA), which have shown the agonistic role of PPARγ and antagonistic role of PPARδ ( 39 ). Therefore, further study is needed to examine whether the role of LJ-1888 as a selective antagonist for A 3 AR is responsible for its anti-atherogenic effects or not.…”

Diallyl Biphenyl-Type Neolignans Have a Pharmacophore of PPARα/γ Dual Modulators

“…hBM-MSCs were purchased from Lonza (Walkersville, MD, USA) and cultured as previously described ( Noh, 2012 ; Yu et al ., 2017 ). hBM-MSCs were maintained in DMEM (1 g/L glucose) supplemented with 10% fetal bovine serum (FBS), antibiotics, and Glutamax TM (Invitrogen, Carlsbad, CA, USA).…”

“…In a phenotype assay, adiponectin secretion-promoting compounds can be identified using the adipogenesis model of hBM-MSCs by supplementing test compounds to the IDX condition. When adiponectin secretion-promoting compounds are screened, target identification experiments primarily focus on investigating their effects on nuclear receptors such as glucocorticoid receptors (GR), PPARs, and liver X receptors (LXR) ( Yu et al ., 2017 ).…”