Conversion of A3 adenosine receptor agonists into selective antagonists by modification of the 5′-ribofuran-uronamide moiety

被引:32
|
作者
Gao, ZG
Joshi, BV
Klutz, AM
Kim, SK
Lee, HW
Kim, HO
Jeong, LS
Jacobson, KA [1 ]
机构
[1] NIDDKD, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA
[2] Ewha Womans Univ, Coll Pharm, Med Chem Lab, Seoul 120750, South Korea
基金
美国国家卫生研究院;
关键词
nucleoside; G protein-coupled receptor; adenylyl cyclase; molecular modeling; radioligand binding;
D O I
10.1016/j.bmcl.2005.10.054
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
引用
收藏
页码:596 / 601
页数:6
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