Shamim M T, Ukena D, Padgett W L, Hong O, Daly J W
Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892.
J Med Chem. 1988 Mar;31(3):613-7. doi: 10.1021/jm00398a020.
A series of 1,3-dipropylxanthines were prepared with a variety of substituents at the 8-position. These included 8-aryl and 8-cycloalkyl groups. Polar carboxylate and carboxamide moieties were introduced as aryl substituents to increase water solubility. 1,3-Dipropyl-8-[2-hydroxy-4-[(carboxymethyl)oxy]phenyl]xanthine provided a functionalized congener with high potency (Ki = 37 nM) and selectivity (54-fold) for A1-adenosine receptors. This congener was used for preparation of a series of other analogues, some with higher potency and some with higher selectivity. 8-Cyclopentyl- and 8-cyclohexyl-1,3-dipropylxanthines were both very potent (Ki = 1-1.5 nM) and selective for A1 receptors, while 8-cycloalkylmethyl analogues were 10-fold less potent, but still very selective for A1 receptors. 8-Piperidinyl and 8-pyrazinyl analogues had very low activities as adenosine receptor antagonists.
制备了一系列在8位带有各种取代基的1,3 - 二丙基黄嘌呤。这些取代基包括8 - 芳基和8 - 环烷基。引入极性的羧酸酯和羧酰胺部分作为芳基取代基以增加水溶性。1,3 - 二丙基 - 8 - [2 - 羟基 - 4 - [(羧甲基)氧基]苯基]黄嘌呤提供了一种对A1 - 腺苷受体具有高效能（Ki = 37 nM）和选择性（54倍）的功能化类似物。该类似物用于制备一系列其他类似物，其中一些具有更高的效能，一些具有更高的选择性。8 - 环戊基 - 和8 - 环己基 - 1,3 - 二丙基黄嘌呤对A1受体都非常有效（Ki = 1 - 1.5 nM）且具有选择性，而8 - 环烷基甲基类似物的效能低10倍，但对A1受体仍具有很高的选择性。8 - 哌啶基和8 - 吡嗪基类似物作为腺苷受体拮抗剂的活性非常低。
