2-Substituted adenosine derivatives: affinity and efficacy at four subtypes of human adenosine receptors
2-Substituted adenosine derivatives: affinity and efficacy at four subtypes of human adenosine receptors
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DOI：
10.1016/j.bcp.2004.06.011
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发表时间：
2004-11-15
影响因子：
5.8
通讯作者：
Jacobson, KA
中科院分区：
文献类型：
--
作者：
Gao, ZG;Mamedova, LK;Jacobson, KA
用放射性配体结合试验和环腺苷酸功能试验，在稳定表达腺苷受体的完整CHO细胞中，评价了广泛的2-取代腺苷衍生物对4种亚型（A（1）、A（2A）、A（2B）和A（3））的亲和力和效力。与以前对N-6-位的研究类似，发现几个2-取代基是A（3）AR活化的关键结构决定因素。以下腺苷2-醚是中等有效的部分激动剂（Ki，nM）：苄基（117）、3-氯苯甲基（72）、2-（3-氯苯基）乙基（41）和2-（2-萘基）乙基（130）。下列腺苷2-醚是A（3）AR拮抗剂：2，2-二苯基乙基、2-（2-降冰片烷）乙基、R-和S-2-苯基丁基和2-（2-氯苯基）乙基。2-（S-2-苯基丁氧基）腺苷作为A（3）AR拮抗剂，使NECA抑制环AMP蓄积的浓度-反应曲线右移，K-B值为212 nM，与其结合亲和力（Ki = 175 nM）相似。与A（3）AR相比，这些2-取代的腺苷衍生物在A（1）AR处的效力通常较低，但完全有效，结合Ki值超过100 nM。当2-苯乙基部分通过醚基连接到腺苷的2-位时（54），比通过胺（310）或硫醚（1960）连接时产生更高的A（3）AR亲和力（Ki，单位为nM）。发现2-[2-（1-萘基）乙氧基]腺苷（Ki = 3.8 nM）是该系列中最有效和选择性（>50倍）的A（2A）激动剂。已经鉴定了混合的A（2A）/A（3）AR激动剂。有趣的是，尽管这些化合物中的大多数在A（2B）AR处非常弱，但发现2-[2-（2-萘基）乙氧基]腺苷（EC 50 = 1.4 μ M）和2-[2-（2-噻吩基）-乙氧基]腺苷（EC 50 = 1.8（M））是相对有效的A（2B）激动剂，尽管不如NECA（EC 50 = 140 nM）有效。(C)2004爱思唯尔公司All rights reserved.
The affinity and efficacy at four subtypes (A(1), A(2A), A(2B) and A(3)) of human adenosine receptors (ARs) of a wide range of 2-substituted adenosine derivatives were evaluated using radioligand binding assays and a cyclic AMP functional assay in intact CHO cells stably expressing these receptors. Similar to previous studies of the N-6-position, several 2-substituents were found to be critical structural determinants for the A(3)AR activation. The following adenosine 2-ethers were moderately potent partial agonists (K-i, nM): benzyl (117), 3-chlorobenzyl (72), 2-(3-chlorophenyl)ethyl (41), and 2-(2-naphthyl)ethyl (130). The following adenosine 2-ethers were A(3)AR antagonists: 2,2-diphenylethyl, 2-(2-norbornan)ethyl, R- and S-2-phenylbutyl, and 2-(2-chlorophenyl)ethyl. 2-(S-2-Phenylbutyloxy)adenosine as an A(3)AR antagonist right-shifted the concentration-response curve for the inhibition by NECA of cyclic AMP accumulation with a K-B value of 212 nM, which is similar to its binding affinity (K-i = 175 nM). These 2-substituted adenosine derivatives were generally less potent at the A(1)AR in comparison to the A(3)AR, but fully efficacious, with binding K-i values over 100 nM. The 2-phenylethyl moiety resulted in higher A(3)AR affinity (K-i in nM) when linked to the 2-position of adenosine through an ether group (54), than when linked through an amine (310) or thioether (1960). 2-[2-(1-Naphthyl)ethyloxyladenosine (K-i = 3.8 nM) was found to be the most potent and selective (>50-fold) A(2A) agonist in this series. Mixed A(2A)/A(3)AR agonists have been identified. Interestingly, although most of these compounds were extremely weak at the A(2B)AR, 2-[2-(2-naphthyl)ethyloxyladenosine (EC50 = 1.4 muM) and 2-[2-(2-thienyl)-ethyloxy]adenosine (EC50 = 1.8 (M) were found to be relatively potent A(2B) agonists, although less potent than NECA (EC50 = 140 nM). (C) 2004 Elsevier Inc. All rights reserved.