A2AR-agonist-1

A2AR-agonist-1 is a potent agonist of adenosine A2A receptor (A2AR) and equilibrative nucleoside transporter1 (ENT1), with K_i values of 4.39 and 3.47, respectively^[1]. By activating A2AR, it regulates the downstream cAMP signaling pathway, while inhibiting ENT1 to reduce cellular adenosine uptake and increase extracellular adenosine concentration, synergistically enhancing the activation effect of A2AR^[2]. As an important ligand for the G protein-coupled receptor family, its dual mechanism of action can effectively regulate intracellular signal transduction, thereby exerting multiple physiological effects such as anti-inflammation, neuroprotection, and improvement of cardiovascular function^[3].

In vitro, treatment of macrophages with A2AR-agonist-1 (1μM) for 2-24 hours induced M2 polarization of macrophages, increased the expression of the anti-inflammatory cytokine IL-10 through the PPARγ-P65 pathway, and inhibited the expression of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)^[4]. Treatment of human corneal epithelial cells with A2AR-agonist-1 (0.001-1μM) for 12 hours significantly promoted corneal epithelial cell proliferation and migration and accelerated wound healing through a biphasic regulatory mechanism of short-term phosphorylation inhibition of YAP activity and long-term activation of YAP nuclear translocation^[5].

In vivo, silicosis model mice were treated with intraperitoneal injection of A2AR-Agonist-1 (0.25mg/kg) for 28 days. By activating A2AR to inhibit the Wnt/β-catenin signaling pathway, the inflammation, fibrosis and epithelial-mesenchymal transition of lung tissue were alleviated^[6]. Intraperitoneal injection of A2AR-agonist-1 (1mg/kg) reduced the expression of E-selectin and ICAM-1 proteins in the aorta, heart, and pulmonary blood vessels of LPS-challenged mice, alleviating corresponding cardiac inflammatory damage ^[7].

References:
[1] Chen JB, Liu EM, Chern TR, et al. Design and synthesis of novel dual-action compounds targeting the adenosine A(2A) receptor and adenosine transporter for neuroprotection. ChemMedChem 2011, 6(8):1390-1400.
[2] Cristalli G, Lambertucci C, Marucci G, et al. A2A adenosine receptor and its modulators: overview on a druggable GPCR and on structure-activity relationship analysis and binding requirements of agonists and antagonists. Curr Pharm Des 2008, 14(15):1525-1552.
[3] Al-Attraqchi OHA, Attimarad M, Venugopala KN, et al. Adenosine A2A Receptor as a Potential Drug Target - Current Status and Future Perspectives. Curr Pharm Des 2019, 25(25):2716-2740.
[4] Mou K-J, Shen K-F, Li Y-L, et al. Adenosine A2A Receptor in Bone Marrow-Derived Cells Mediated Macrophages M2 Polarization via PPARγ-P65 Pathway in Chronic Hypoperfusion Situation. Frontiers in Aging Neuroscience 2022, Volume 13 - 2021.
[5] Sun Q, Jiang N, Yao R, et al. An agonist of the adenosine A(2A) receptor, CGS21680, promotes corneal epithelial wound healing via the YAP signalling pathway. Br J Pharmacol 2024, 181(19):3779-3795.
[6] Tian Y, Xia J, Yang G, et al. A2aR inhibits fibrosis and the EMT process in silicosis by regulating Wnt/β-catenin pathway. Ecotoxicol Environ Saf 2023, 249:114410.
[7] Li Y, Chen T, Cheang I, et al. Macrophage A2aR Alleviates LPS-Induced Vascular Endothelial Injury and Inflammation via Inhibiting M1 Polarisation and Oxidative Stress. J Cell Mol Med 2025, 29(5):e70458.

A2AR-agonist-1是腺苷A2A受体（A2AR）和平衡型核苷转运体1（ENT1）的强效激动剂，其Ki 值分别为 4.39 和 3.47^[1]。通过激活A2AR，它可调节下游环磷酸腺苷（cAMP）信号通路，同时抑制 ENT1以减少细胞对腺苷的摄取，增加细胞外腺苷浓度，协同增强A2AR的激活效应^[2]。作为 G 蛋白偶联受体家族的重要配体，其双重作用机制可有效调节细胞内信号转导，从而发挥抗炎、神经保护和改善心血管功能等多种生理效应^[3]。

在体外，用A2AR-agonist-1（1μM）处理巨噬细胞 0.5 小时可诱导巨噬细胞向M2型极化，通过PPARγ-P65通路增加抗炎细胞因子IL-10的表达，并抑制肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）的表达^[4]。使用A2AR-agonist-1（0.001-1μM）处理人角膜上皮细胞12h，通过短期磷酸化抑制 YAP 活性、长期激活YAP核转位的双相调控机制，显著促进角膜上皮细胞的增殖与迁移，加速伤口愈合^[5]。

在体内，使用 A2AR-agonist-1（0.25mg/kg）腹腔注射治疗矽肺模型小鼠28天，通过激活A2AR抑制Wnt/β-连环蛋白信号通路，从而减轻肺组织炎症、纤维化及上皮间充质转化^[6]。A2AR-agonist-1（1mg/kg）通过腹腔注射减少了LPS攻击小鼠的主动脉、心脏和肺血管中E-选择素和ICAM-1蛋白的表达，减轻了相应的心脏炎症损伤^[7]。