Conversion of A3 adenosine receptor agonists into selective antagonists by modification of the 5′-ribofuran-uronamide moiety
Conversion of A3 adenosine receptor agonists into selective antagonists by modification of the 5′-ribofuran-uronamide moiety
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DOI：
10.1016/j.bmcl.2005.10.054
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发表时间：
2006-02-01
影响因子：
2.7
通讯作者：
Jacobson, KA
中科院分区：
文献类型：
--
作者：
Gao, ZG;Joshi, BV;Jacobson, KA
A(3) 腺苷受体 (AR) 的高选择性激动剂 Cl-IB-MECA（2-氯-N-6-(3-碘苄基)-5'-N-甲基羧酰胺腺苷）及其 4'-硫代类似物，只需在 5'-糖醛酰胺位置上添加第二个 N-甲基，即可成功转化为选择性拮抗剂。 2-氯-5'-(N,N-二甲基)脲酰胺类似物与人 A(3)AR 结合但不激活，K-i 值为 29 nM (4'-O) 和 15 nM (4'-S)，显示出比 A(1)、A(2A) 和 A(2B) AR 多 100 倍的选择性。 Schild 分析证明了竞争性拮抗作用。 2-(二甲氨基)-5'-(N,N-二甲基)脲酰胺基取代也保留了A3AR选择性，但降低了亲和力。 (c) 2005 Elsevier Ltd. 保留所有权利。
The highly selective agonists of the A(3) adenosine receptor (AR), Cl-IB-MECA (2-chloro-N-6-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine), and its 4'-thio analogue, were successfully converted into selective antagonists simply by appending a second N-methyl group on the 5'-uronamide position. The 2-chloro-5'-(N,N-dimethyl)uronamido analogues bound to, but did not activate, the human A(3)AR, with K-i values of 29 nM (4'-O) and 15 nM (4'-S), showing > 100-fold selectivity over A(1), A(2A), and A(2B)ARs. Competitive antagonism was demonstrated by Schild analysis. The 2-(dimethylamino)-5'-(N,N-dimethyl)uronamido substitution also retained A3AR selectivity but lowered affinity. (c) 2005 Elsevier Ltd. All rights reserved.