通过修饰5'-呋喃核糖脲酰胺部分将A3腺苷受体激动剂转化为选择性拮抗剂。
Conversion of A3 adenosine receptor agonists into selective antagonists by modification of the 5'-ribofuran-uronamide moiety.
作者信息
Gao Zhan-Guo, Joshi Bhalchandra V, Klutz Athena M, Kim Soo-Kyung, Lee Hyuk Woo, Kim Hea Ok, Jeong Lak Shin, Jacobson Kenneth A
机构信息
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
出版信息
Bioorg Med Chem Lett. 2006 Feb;16(3):596-601. doi: 10.1016/j.bmcl.2005.10.054. Epub 2005 Nov 10.
Abstract
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 A(3)AR selectivity but lowered affinity.
摘要
A3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-甲基甲酰胺基腺苷）及其4'-硫代类似物，只需在5'-脲酰胺位置上再连接一个N-甲基基团，就能成功转化为选择性拮抗剂。2-氯-5'-(N,N-二甲基)脲酰胺类似物与人类A3AR结合，但不激活它，其抑制常数（Ki）值分别为29 nM（4'-O）和15 nM（4'-S），对A1、A2A和A2B ARs的选择性大于100倍。通过Schild分析证实了竞争性拮抗作用。2-(二甲基氨基)-5'-(N,N-二甲基)脲酰胺取代也保留了A3AR选择性，但降低了亲和力。
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