Jung Kwan-Young, Kim Soo-Kyung, Gao Zhan-Guo, Gross Ariel S, Melman Neli, Jacobson Kenneth A, Kim Yong-Chul
Laboratory of Drug Discovery, Department of Life Science, Kwangju Institute of Science and Technology, Gwangju 500-712, South Korea.
Bioorg Med Chem. 2004 Feb 1;12(3):613-23. doi: 10.1016/j.bmc.2003.10.041.
4-(4-Methoxyphenyl)-2-aminothiazole and 3-(4-methoxyphenyl)-5-aminothiadiazole derivatives have been synthesized and evaluated as selective antagonists for human adenosine A3 receptors. A methoxy group in the 4-position of the phenyl ring and N-acetyl or propionyl substitutions of the aminothiazole and aminothiadiazole templates displayed great increases of binding affinity and selectivity for human adenosine A3 receptors. The most potent A3 antagonist of the present series, N-[3-(4-methoxy-phenyl)-[1,2,4]thiadiazol-5-yl]-acetamide (39) exhibiting a Ki value of 0.79 nM at human adenosine A3 receptors, showed antagonistic property in a functional assay of cAMP biosynthesis involved in one of the signal transduction pathways of adenosine A3 receptors. Molecular modeling study of conformation search and receptor docking experiments to investigate the dramatic differences of binding affinities between two regioisomers of thiadiazole analogues, (39) and (42), suggested possible binding mechanisms in the binding pockets of adenosine receptors.
已合成4-(4-甲氧基苯基)-2-氨基噻唑和3-(4-甲氧基苯基)-5-氨基噻二唑衍生物，并将其作为人腺苷A3受体的选择性拮抗剂进行评估。苯环4位上的甲氧基以及氨基噻唑和氨基噻二唑模板的N-乙酰基或丙酰基取代对人腺苷A3受体的结合亲和力和选择性有显著提高。本系列中最有效的A3拮抗剂N-[3-(4-甲氧基苯基)-[1,2,4]噻二唑-5-基]-乙酰胺(39)在人腺苷A3受体上的Ki值为0.79 nM，在腺苷A3受体信号转导途径之一的cAMP生物合成功能试验中表现出拮抗特性。通过构象搜索的分子建模研究和受体对接实验来研究噻二唑类似物(39)和(42)的两种区域异构体之间结合亲和力的显著差异，提示了腺苷受体结合口袋中的可能结合机制。
