Szymańska Ewa, Drabczyńska Anna, Karcz Tadeusz, Müller Christa E, Köse Meryem, Karolak-Wojciechowska Janina, Fruziński Andrzej, Schabikowski Jakub, Doroz-Płonka Agata, Handzlik Jadwiga, Kieć-Kononowicz Katarzyna
Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Bioorg Med Chem. 2016 Sep 15;24(18):4347-4362. doi: 10.1016/j.bmc.2016.07.028. Epub 2016 Jul 18.
A new series of 32 pyrimido- and 5 tetrahydropyrazino[2,1-f]purinediones was obtained and evaluated for their adenosine receptors (ARs) affinities. The 1,3-dibutyl derivative of 9-(4-(2-(dimethylamino)ethoxy)phenyl)-6,7,8,9-tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)-dione was found to be the most potent A1 AR antagonist of the present series, showing selectivity over the other AR subtypes. The structure-activity for the obtained purinediones was established. Docking experiments of the investigated library to homology models of the human and rat A1 and A2A ARs allowed to compare the expected binding modes for selected compounds. The detailed analysis of binding cavities within individual AR subtypes indicated small but significant structural variations that may underlie the observed differences in binding affinities of purinediones at particular subtypes and species.
合成了一系列新的32种嘧啶并[1,2 - f]嘌呤二酮和5种四氢吡嗪并[2,1 - f]嘌呤二酮，并对它们与腺苷受体（ARs）的亲和力进行了评估。发现9-(4-(2-(二甲氨基)乙氧基)phenyl)-6,7,8,9 - 四氢嘧啶并[1,2 - f]嘌呤 - 2,4(1H,3H)-二酮的1,3 - 二丁基衍生物是本系列中最有效的A1 AR拮抗剂，对其他AR亚型具有选择性。确定了所获得的嘌呤二酮的构效关系。将研究文库与人和大鼠A1和A2A ARs的同源模型进行对接实验，以便比较所选化合物的预期结合模式。对各个AR亚型内结合腔的详细分析表明，存在微小但显著的结构差异，这些差异可能是观察到的嘌呤二酮在特定亚型和物种上结合亲和力差异的基础。
