Selective A3 adenosine receptor antagonists derived from nucleosides containing a bicyclo[3.1.0]hexane ring system
Selective A3 adenosine receptor antagonists derived from nucleosides containing a bicyclo[3.1.0]hexane ring system
复制标题
DOI：
10.1016/j.bmc.2008.08.007
复制
发表时间：
2008-09-15
影响因子：
3.5
通讯作者：
Jacobson, Kenneth A.
中科院分区：
文献类型：
--
作者：
Melman, Artem;Wang, Ben;Jacobson, Kenneth A.
我们制备了腺苷的5'-修饰衍生物和相应的(N)-methanocarba核苷系列，其含有双环[3.1.0]己烷环系统代替核糖部分。这些化合物在腺苷受体 (AR) 的三种亚型的结合测定中以及 A(3)AR 的功能测定中进行了检查。 modi 降低了一组含有 5'-糖醛酰胺部分的 9-核苷衍生物的氢键结合能力。 NH的阳离子；然而，这些衍生物没有表现出作为选择性 A(3)AR 拮抗剂所需的活性，如 5'-N,N-二甲基脲酰胺。然而，缺乏 4'-羟甲基的截短 (N)-methanocarba 类似物是人 A(3) AR 的高效和选择性拮抗剂。这些化合物是通过 5'-羧基中间体的还原自由基脱羧作用从 D-核糖合成的。一种效率较低的合成方法是从 L-核糖开始，这与已发表的 (N)-methanocarba A(3)AR 激动剂的合成类似。化合物33b-39b（N-6-3-卤代苄基和相关的芳烷基衍生物）是有效的A(3)AR拮抗剂，其结合K-i值为0.7-1.4nM。在 [S-35] GTP gamma S 结合的功能测定中，33b（3-碘苄基）完全抑制 NECA 的刺激，K-B 为 8.9 nM。因此，已经描述了一系列高效且选择性的A(3)AR拮抗剂。 (C) 2008 Elsevier Ltd. 保留所有权利。
We have prepared 5 '-modified derivatives of adenosine and a corresponding (N)-methanocarba nucleoside series containing a bicyclo[3.1.0] hexane ring system in place of the ribose moiety. The compounds were examined in binding assays at three subtypes of adenosine receptors (ARs) and in functional assays at the A(3)AR. The H-bonding ability of a group of 9-riboside derivatives containing a 5 '-uronamide moiety was reduced by modi. cation of the NH; however these derivatives did not display the desired activity as selective A(3)AR antagonists, as occurs with 5 '-N,N-dimethyluronamides. However, truncated (N)-methanocarba analogues lacking a 4 '-hydroxymethyl group were highly potent and selective antagonists of the human A(3) AR. The compounds were synthesized from D-ribose using a reductive free radical decarboxylation of a 5 '-carboxy intermediate. A less efficient synthetic approach began with L-ribose, which was similar to the published synthesis of (N)-methanocarba A(3)AR agonists. Compounds 33b-39b (N-6-3-halobenzyl and related arylalkyl derivatives) were potent A(3)AR antagonists with binding K-i values of 0.7-1.4 nM. In a functional assay of [S-35] GTP gamma S binding, 33b (3-iodobenzyl) completely inhibited stimulation by NECA with a K-B of 8.9 nM. Thus, a highly potent and selective series of A(3)AR antagonists has been described. (C) 2008 Elsevier Ltd. All rights reserved.