STRUCTURE-ACTIVITY-RELATIONSHIPS FOR DERIVATIVES OF ADENOSINE-5'-TRIPHOSPHATE AS AGONISTS AT P-2 PURINOCEPTORS - HETEROGENEITY WITHIN P-2X AND P-2Y SUBTYPES
STRUCTURE-ACTIVITY-RELATIONSHIPS FOR DERIVATIVES OF ADENOSINE-5'-TRIPHOSPHATE AS AGONISTS AT P-2 PURINOCEPTORS - HETEROGENEITY WITHIN P-2X AND P-2Y SUBTYPES
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DOI：
10.1002/ddr.430310308
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发表时间：
1994-03-01
影响因子：
3.8
通讯作者：
JACOBSON, KA
中科院分区：
文献类型：
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作者：
BURNSTOCK, G;FISCHER, B;JACOBSON, KA
研究了几种腺嘌呤核苷酸类似物在P-2X-和P-2Y-嘌呤受体上的构效关系。通过对ATP分子进行结构修饰，包括取代嘌呤环(C2、C8、N1和N-6-取代基，以及取代腺嘌呤的尿苷碱)、核糖部分(2‘和3’-位)和三磷酸基团(较低的磷酸盐、桥接氧取代和环化)，制备了化合物。在豚鼠结肠带、兔主动脉内皮细胞、兔肠系膜动脉平滑肌和火鸡红细胞膜上测定了P-2Y-嘌呤受体的药理活性。本文测定了兔隐动脉、豚鼠输精管和膀胱的P-2X-嘌呤受体的活性。一些类似物对P-2X-或P-2Y-嘌呤受体表现出选择性，甚至专一性。某些类似物在P-2X或P-2Y-嘌呤受体超家族中表现出选择性或特异性，为可能的亚类提供了线索。例如，8-(6-氨基己氨基)-三磷酸腺苷和2‘，3’-异亚丙基腺苷对豚鼠结肠带、兔主动脉和火鸡红细胞的内皮P-2Y-嘌呤受体比P-2Y-嘌呤受体具有选择性。这两个化合物在P-2X-嘌呤受体上都没有活性。强效激动剂N-6-甲基-三磷酸腺苷和稍弱的激动剂2‘-脱氧-三磷酸腺苷对豚鼠结肠带绦虫的P-2Y-嘌呤受体有选择性，但对P-2X-嘌呤受体和血管P-2Y-嘌呤受体无效。3‘-苄氨基-3’-脱氧三磷酸腺苷对豚鼠输精管和膀胱的P-2X-嘌呤受体有很强的作用，对兔隐动脉无作用，对P-2Y受体无作用。这些数据表明，可以开发特定的化合物来激活P-2X-和P-2Y-嘌呤受体类的假定亚型。(C)1994年Wiley-Liss，Inc.
The structure-activity relationships for a variety of adenine nucleotide analogues at P-2X- and P-2Y-purinoceptors were investigated. Compounds formed by structural modifications of the ATP molecule including substitutions of the purine ring (C2, C8, N1, and N-6-substituents, and a uridine base instead of adenine), the ribose moiety (2' and 3'-positions), and the triphosphate group (lower phosphates, bridging oxygen substitution, and cyclization) were prepared. Pharmacological activity at P-2Y-purinoceptors was assayed in the guinea pig taenia coli, endothelial cells of the rabbit aorta, smooth muscle of the rabbit mesenteric artery, and turkey erythrocyte membranes. Activity at P-2X-purinoceptors was assayed in the rabbit saphenous artery and the guinea-pig vas deferens and urinary bladder. Some of the analogues displayed selectivity, or even specificity, for either the P-2X- or the P-2Y-purinoceptors. Certain analogues displayed selectivity or specificity within the P-2X- or P-2Y-purinoceptor superfamilies, giving hints about possible subclasses. For example, 8-(6-aminohexylamino)ATP and 2',3'-isopropylidene-AMP were selective for endothelial P-2Y-purinoceptors over P-2Y-purinoceptors in the guinea pig taenia coli, rabbit aorta, and turkey erythrocytes. These compounds were both inactive at P-2X-purinoceptors. The potent agonist N-6-methyl ATP and the somewhat less potent agonist 2'-deoxy-ATP were selective for P-2Y-purinoceptors in the guinea pig taenia coli, but were inactive at P-2X-purinoceptors and the vascular P-2Y-purinoceptors. 3'-Benzylamino-3'-deoxyATP was very potent at the P-2X-purinoceptors in the guinea pig vas deferens and bladder, but not in the rabbit saphenous artery and was inactive at P-2Y receptors. These data suggest that specific compounds can be developed that can be utilized to activate putative subtypes of the P-2X- and P-2Y-purinoceptor classes. (C) 1994 Wiley-Liss, Inc.