Xia Yan, Zheng Xiliang, Wang Erkang, Li Dongfeng, Hou Ruibin, Wang Jin
State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry Chinese Academy of Sciences, Renmen Street, Changchun 130022, People's Republic of China.
College of Chemistry and Life Science, Changchun University of Technology, Yanan Street No. 2055, Changchun 130012, People's Republic of China.
R Soc Open Sci. 2018 Feb 7;5(2):171596. doi: 10.1098/rsos.171596. eCollection 2018 Feb.
Adenosine is an endogenous modulator exerting its functions through the activation of four adenosine receptor (AR) subtypes, termed A, A, A and A, which belong to the G-protein-coupled receptor superfamily. The human AAR (hAAR) subtype is implicated in several cytoprotective functions. Therefore, hAAR modulators, and in particular agonists, are sought for their potential application as anti-inflammatory, anti-cancer and cardioprotective agents. Here, we prepared novel adenosine derivatives with indole moiety as hAAR ligands. According to the biological assay, we found that 2-substituents were critical structural determinants for AAR ligands ( = 111 nM). The observed structure-affinity relationships of this class of ligands were also exhaustively rationalized using the molecular modelling approach. This allows the investigation on the binding mode of the potential compound in the ligand-binding pocket of the human A receptor. The results demonstrated that can interact with the ASN250, GLN167, PHE168 and VAL178 through hydrogen bonding, which are shown to be important for ligand-receptor interaction.
腺苷是一种内源性调节剂，通过激活四种腺苷受体（AR）亚型发挥其功能，这四种亚型分别称为A1、A2A、A2B和A3，它们属于G蛋白偶联受体超家族。人类A2A受体（hA2AR）亚型与多种细胞保护功能有关。因此，人们正在寻找hA2AR调节剂，尤其是激动剂，以探索其作为抗炎、抗癌和心脏保护剂的潜在应用。在此，我们制备了具有吲哚部分的新型腺苷衍生物作为hA2AR配体。根据生物学测定，我们发现2-取代基是A2AR配体的关键结构决定因素（EC50 = 111 nM）。这类配体观察到的结构-亲和力关系也通过分子建模方法进行了详尽的合理化解释。这使得我们能够研究潜在化合物在人类A2A受体配体结合口袋中的结合模式。结果表明，[化合物名称未给出]可以通过氢键与ASN250、GLN167、PHE168和VAL178相互作用，这些被证明对配体-受体相互作用很重要。
