TY - JOUR
T1 - Polypharmacology of N6-(3-Iodobenzyl)adenosine-5′-N-methyluronamide (IB-MECA) and Related A3 Adenosine Receptor Ligands
T2 - Peroxisome Proliferator Activated Receptor (PPAR) γ Partial Agonist and PPARδ Antagonist Activity Suggests Their Antidiabetic Potential
AU - Yu, Jinha
AU - Ahn, Seyeon
AU - Kim, Hee Jin
AU - Lee, Moonyoung
AU - Ahn, Sungjin
AU - Kim, Jungmin
AU - Jin, Sun Hee
AU - Lee, Eunyoung
AU - Kim, Gyudong
AU - Cheong, Jae Hoon
AU - Jacobson, Kenneth A.
AU - Jeong, Lak Shin
AU - Noh, Minsoo
N1 - Funding 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.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/9/14
Y1 - 2017/9/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85029483448&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.7b00805
DO - 10.1021/acs.jmedchem.7b00805
M3 - Article
C2 - 28799755
AN - SCOPUS:85029483448
SN - 0022-2623
VL - 60
SP - 7459
EP - 7475
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 17
ER -
