125I-labeled 8-phenylxanthine derivatives: antagonist radioligands for adenosine A1 receptors.
125I-labeled 8-phenylxanthine derivatives: antagonist radioligands for adenosine A1 receptors.
复制标题
125I标记的8-苯基黄嘌呤衍生物：腺苷A1受体的拮抗放射性配体。
DOI：
10.1021/jm00399a010
复制
发表时间：
1988
影响因子：
7.3
通讯作者：
Daluge,SM
中科院分区：
文献类型：
--
作者：
Linden,J;Patel,A;Earl,CQ;Craig,RH;Daluge,SM
合成了一系列8-苯基黄嘌呤衍生物，在帕拉苯基位置上具有氧乙酸，以增加水溶性并使黄嘌呤环的1-或3-位上的非特异性结合和可碘化基团最小化。研究了这些化合物与牛和大鼠脑的A1腺苷受体和人血小板的A2受体结合的构效关系。添加芳胺或光敏芳基叠氮基团的3-位的黄嘌呤有或没有碘化对A1的结合亲和力几乎没有影响，而在1-位的取代导致A1的结合亲和力大大降低。在黄嘌呤的3-位添加氨基苄基对A2结合亲和力的影响不大，但3-氨基苯乙基取代降低了A2结合亲和力。两个酸性3-（芳氨基）-8-苯基黄嘌呤衍生物标记与/sup 125/I和评估作为A1受体放射性配体。新的放射性配体与A1受体结合，KD值为1-1.25 nM。特异性结合占总结合的80%以上。高浓度的NaCl或其他盐增加了酸性但不是中性拮抗剂的结合亲和力，这表明离子化黄嘌呤和受体之间的相互作用可能会受到离子强度变化的显着影响。基于与这些拮抗剂的结合研究和与激动剂（/sup 125/I）N6-（4-氨基-3-碘苄基）腺苷的同位素稀释，已经鉴定了A1受体的多种激动剂亲和力状态。
A series of 8-phenylxanthine derivatives has been synthesized with oxyacetic acid on the para phenyl position to increase aqueous solubility and minimize nonspecific binding and iodinatable groups on the 1- or 3-position of the xanthine ring. The structure-activity relationship for binding of these compounds to A1 adenosine receptors of bovine and rat brain and A2 receptors of human platelets was examined. The addition of arylamine or photosensitive aryl azide groups to the 3-position of xanthine had little effect on A1 binding affinity with or without iodination, whereas substitutions at the 1-position caused greatly reduced A1 binding affinity. The addition of an aminobenzyl group to the 3-position of the xanthine had little effect on A2 binding affinity, but 3-aminophenethyl substitution decreased A2 binding affinity. Two acidic 3-(arylamino)-8-phenylxanthine derivatives were labeled with /sup 125/I and evaluated as A1 receptor radioligands. The new radioligands bound to A1 receptors with KD values of 1-1.25 nM. Specific binding represented over 80% of total binding. High concentrations of NaCl or other salts increased the binding affinity of acidic but not neutral antagonists, suggesting that interactions between ionized xanthines and receptors may be affected significantly by changes in ionic strength. On the basis of binding studies with these antagonists and isotope dilution with the agonist (/sup 125/I)N6-(4-amino-3-iodobenzyl)adenosine, multiple agonist affinity states of A1 receptors have been identified.