N6-Cycloalkyl- and N6-Bicycloalkyl-C5′(C2′)-modified Adenosine Derivatives as High-Affinity and Selective Agonists at the Human A1 Adenosine Receptor with Antinociceptive Effects in Mice
N6-Cycloalkyl- and N6-Bicycloalkyl-C5′(C2′)-modified Adenosine Derivatives as High-Affinity and Selective Agonists at the Human A1 Adenosine Receptor with Antinociceptive Effects in Mice
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DOI：
10.1021/jm801456g
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发表时间：
2009-04-23
影响因子：
7.3
通讯作者：
Grifantini, Mario
中科院分区：
文献类型：
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作者：
Franchetti, Palmarisa;Cappellacci, Loredana;Grifantini, Mario
为了进一步研究新的有效的和选择性的人A（1）腺苷受体激动剂，我们合成了一系列5 ′-氯-5 ′-脱氧-和5 ′-（2-氟苯硫基）-5 ′-脱氧-N-6-环烷基（双环烷基）-取代的腺苷和2 ′-C-甲基腺苷衍生物。评价了这些化合物对人A1、A（2A）、A（2B）和A（3）腺苷受体的亲和力和功效。在N-6-环戊基-和N-6-（内-β 2-基）腺苷衍生物系列中，5 '-氯-5'-脱氧-CPA（1）和5 '-氯-5'-脱氧-（+/-）-ENBA（3）在亚纳摩尔范围内对hA（1）显示出最高的亲和力和相对于其他人类受体亚型的相关选择性。通过分子模拟分析，证明了与母体5 ′-羟基化合物CPA和（+/-）-ENBA相比，5 ′-氯-5 ′-脱氧核糖核苷衍生物1和3对hA（1）AR的亲和力和选择性更高。在小鼠福尔马林试验中评价镇痛活性的5 ′-氯-5 ′-脱氧-（+/-）-ENBA被发现抑制由爪内注射1 - 2 mg/kg i. p.的剂量的福尔马林诱导的疼痛反应的第一或第二阶段。
To further investigate new potent and selective human A(1) adenosine receptor agonists, we have synthesized a series of 5'-chloro-5'-deoxy- and 5'-(2-fluorophenylthio)-5'-deoxy-N-6-cycloalkyl(bicycloalkyl)-substituted adenosine and 2'-C-methyladenosine derivatives. These compounds were evaluated for affinity and efficacy at human A,, A(2A), A(2B), and A(3) adenosine receptors. In the series of N-6-cyclopentyl- and N-6-(endo-norborn2-yl)adenosine derivatives, 5'-chloro-5'-deoxy-CPA (1) and 5'-chloro-5'-deoxy-(+/-)-ENBA (3) displayed the highest affinity in the subnanomolar range and relevant selectivity for hA(1) vs the other human receptor subtypes. The higher affinity and selectivity of 5'-chloro-5'-deoxyribonucleoside derivatives 1 and 3 for hA(1) AR vs hA(3) AR compared to that of the parent 5'-hydroxy compounds CPA and (+/-)-ENBA was rationalized by a molecular modeling analysis. 5'-Chloro-5'-deoxy-(+/-)-ENBA, evaluated for analgesic activity in the formalin test in mice, was found to inhibit the first or the second phases of the nocifensive response induced by intrapaw injection of formalism at doses ranging between 1 and 2 mg/kg i.p.