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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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-08-28 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00805 Jinha Yu , Seyeon Ahn , Hee Jin Kim 1 , Moonyoung Lee , Sungjin Ahn , Jungmin Kim , Sun Hee Jin , Eunyoung Lee , Gyudong Kim , Jae Hoon Cheong 1 , Kenneth A. Jacobson 2 , Lak Shin Jeong , Minsoo Noh
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-08-28 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00805 Jinha Yu , Seyeon Ahn , Hee Jin Kim 1 , Moonyoung Lee , Sungjin Ahn , Jungmin Kim , Sun Hee Jin , Eunyoung Lee , Gyudong Kim , Jae Hoon Cheong 1 , Kenneth A. Jacobson 2 , Lak Shin Jeong , Minsoo Noh
Affiliation
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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.
中文翻译：
的Polypharmacology Ñ 6 - （3-碘苄基）腺苷-5'- Ñ -methyluronamide（IB-MECA）和相关的甲3腺苷受体配体：过氧化物酶体增殖物激活受体（PPAR）γ部分激动剂和PPARδ拮抗剂活性表明其抗糖尿病潜在
检查了3 A腺苷受体（AR）配体，包括A 3 AR激动剂，N 6-（3-碘苄基）腺苷-5'- N-甲基脲酰胺（1a，IB-MECA）在人骨髓间充质干细胞中产生的脂联素（ hBM-MSC）。在此模型中，1a可以显着增加脂联素的产生，这与胰岛素敏感性的提高有关。但是，A 3 AR拮抗剂也促进了hBM-MSC中脂联素的产生，表明A 3AR途径可能不直接参与脂联素的促进活性。在目标反褶积研究中，它们的脂联素促进活性与它们与过氧化物酶体增殖物激活受体（PPAR）γ和PPARδ的结合活性显着相关。它们既充当PPARγ部分激动剂，又充当PPARδ拮抗剂。在糖尿病小鼠模型中，1a及其结构类似物A 3 AR拮抗剂可显着降低血清葡萄糖和甘油三酸酯的水平，从而支持其抗糖尿病的潜力。这些发现表明，这些化合物的多药效团可以提供其针对多种人类疾病的多能功效的治疗见解。
更新日期：2017-08-28
中文翻译：
的Polypharmacology Ñ 6 - （3-碘苄基）腺苷-5'- Ñ -methyluronamide（IB-MECA）和相关的甲3腺苷受体配体：过氧化物酶体增殖物激活受体（PPAR）γ部分激动剂和PPARδ拮抗剂活性表明其抗糖尿病潜在
检查了3 A腺苷受体（AR）配体，包括A 3 AR激动剂，N 6-（3-碘苄基）腺苷-5'- N-甲基脲酰胺（1a，IB-MECA）在人骨髓间充质干细胞中产生的脂联素（ hBM-MSC）。在此模型中，1a可以显着增加脂联素的产生，这与胰岛素敏感性的提高有关。但是，A 3 AR拮抗剂也促进了hBM-MSC中脂联素的产生，表明A 3AR途径可能不直接参与脂联素的促进活性。在目标反褶积研究中，它们的脂联素促进活性与它们与过氧化物酶体增殖物激活受体（PPAR）γ和PPARδ的结合活性显着相关。它们既充当PPARγ部分激动剂，又充当PPARδ拮抗剂。在糖尿病小鼠模型中，1a及其结构类似物A 3 AR拮抗剂可显着降低血清葡萄糖和甘油三酸酯的水平，从而支持其抗糖尿病的潜力。这些发现表明，这些化合物的多药效团可以提供其针对多种人类疾病的多能功效的治疗见解。
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