Grahner B, Winiwarter S, Lanzner W, Müller C E
Eberhard-Karls-Universität Tübingen, Pharmazeutisches Institut, Germany.
J Med Chem. 1994 May 13;37(10):1526-34. doi: 10.1021/jm00036a019.
A set of 22 9-deazaxanthines (pyrrolo[3,2-d]pyrimidine-2,4-diones) and three 7-deazaxanthines (pyrrolo[2,3-d]pyrimidine-2,4-diones) with various substituents in the 1-, 3-, 7- or 9-, and 8-positions was synthesized and investigated in A1 and A2a adenosine receptor binding assays at rat brain cortical membranes and rat brain striatal membranes, respectively. 9-Deazaxanthines showed structure-activity relationships that were similar to those of xanthines. They were about equipotent to the corresponding xanthines at A2a adenosine receptors. 9-Deazaxanthines were generally at least 2-3-fold more potent than xanthines at A1 receptors and therefore exhibited higher A1 selectivities compared to the xanthines. 1,3-Dimethyl-8-(2-naphthyl)-9- deazaxanthine (19e) showed high affinity (Ki = 26 nM) and selectivity for A1 adenosine receptors. A hydroxyl function at N7 of 9-deazaxanthines was unfavorable for A1 and A2a receptor binding. 7-Deazaxanthines were considerably less potent compared to xanthines and to 9-deazaxanthines at both receptor subtypes.
合成了一组在1、3、7或9位以及8位带有各种取代基的22种9-脱氮黄嘌呤（吡咯并[3,2-d]嘧啶-2,4-二酮）和3种7-脱氮黄嘌呤（吡咯并[2,3-d]嘧啶-2,4-二酮），并分别在大鼠脑皮质膜和大鼠脑纹状体膜的A1和A2a腺苷受体结合试验中进行了研究。9-脱氮黄嘌呤显示出与黄嘌呤相似的构效关系。它们在A2a腺苷受体上与相应的黄嘌呤效力相当。9-脱氮黄嘌呤在A1受体上通常比黄嘌呤至少强2至3倍，因此与黄嘌呤相比表现出更高的A1选择性。1,3-二甲基-8-(2-萘基)-9-脱氮黄嘌呤（19e）对A1腺苷受体显示出高亲和力（Ki = 26 nM）和选择性。9-脱氮黄嘌呤N7位的羟基官能团对A1和A2a受体结合不利。7-脱氮黄嘌呤在两种受体亚型上的效力与黄嘌呤和9-脱氮黄嘌呤相比都要低得多。
