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

J Med Chem. 2017 Sep 14;60(17):7459-7475. doi: 10.1021/acs.jmedchem.7b00805. Epub 2017 Aug 28.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / chemistry
  • Adenosine / pharmacology
  • Adenosine / therapeutic use
  • Adenosine A3 Receptor Agonists / chemistry
  • Adenosine A3 Receptor Agonists / pharmacology
  • Adenosine A3 Receptor Agonists / therapeutic use*
  • Adenosine A3 Receptor Antagonists / chemistry
  • Adenosine A3 Receptor Antagonists / pharmacology
  • Adenosine A3 Receptor Antagonists / therapeutic use
  • Adiponectin / metabolism
  • Animals
  • Cell Line
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / metabolism
  • Humans
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use*
  • Insulin Resistance
  • Ligands
  • Male
  • Mice
  • Mice, Inbred C57BL
  • PPAR delta / antagonists & inhibitors*
  • PPAR delta / metabolism
  • PPAR gamma / agonists*
  • PPAR gamma / metabolism
  • Polypharmacology
  • Receptor, Adenosine A3 / metabolism

Substances

  • Adenosine A3 Receptor Agonists
  • Adenosine A3 Receptor Antagonists
  • Adiponectin
  • Hypoglycemic Agents
  • Ligands
  • PPAR delta
  • PPAR gamma
  • Receptor, Adenosine A3
  • N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine
  • Adenosine