Synthesis and biological activity of new potential agonists for the human adenosine A2A receptor
Synthesis and biological activity of new potential agonists for the human adenosine A2A receptor
复制标题
DOI：
10.1021/jm031143
复制
发表时间：
2004-07-29
影响因子：
7.3
通讯作者：
Guerrero, A
中科院分区：
文献类型：
--
作者：
Bosch, MP;Campos, F;Guerrero, A
新的腺苷衍生物已经被合成，并被测试为腺苷受体的潜在激动剂。化合物2-6在母体化合物1的苯环对位引入了几种取代基(给电子、吸电子和卤素)，化合物7缺少氨基醇1的羟基。在用重组人A(1)、A(2A)、A(2B)和A(3)受体进行的放射配基结合分析中，所有化合物对A(1)和A(2B)受体的亲和力都很低或可以忽略不计，但化合物3、5和7对A2A受体表现出很强的亲和力，K-I值为1-5 nM。溴代衍生物3的选择性为A(1)/A(2A)=62和A(3)/A(2A)=16，而羟基(化合物5)的存在使A(1)/A(2A)和A(3)/A(2A)的选择性分别提高了120倍和28倍。当甲氧基衍生物4的侧链上没有羟基时(化合物7)，与A(2A)的结合亲和力增加到1 nm，对A(1)和A(3)的选择性比分别提高到356倍和100倍。在转染人A2A和A(2B)受体的中国仓鼠卵巢细胞中，除氯代衍生物2外，大多数化合物对A2A受体都有显著的活性，EC50值在1.4~8.8 nM之间。化合物2的A(2B)/A(2A)比值为48，而化合物7的A(2B)/A(2A)比值仅为9。化合物1、3、5和7在大鼠和豚鼠的主动脉上的选择性也比NECA高100倍。在卡巴胆碱预收缩的豚鼠气管环上，化合物2和4的作用强于腺苷(100倍)和NECA(10倍)，而化合物1和7的作用与NECA相似。A(2)、A(2A)和A(2B)受体拮抗剂3，7-二甲基-L-炔丙基黄嘌呤、8-(3-氯苯乙烯基)咖啡因和四氧嘧啶可显著抑制化合物1、2和4引起的气管松弛，但这些化合物对腺苷受体均无选择性。
New adenosine derivatives have been synthesized and tested as putative agonists of adenosine receptors. Compounds 2-6 derive from the introduction of several types of substituents (electron donating, electron withdrawing, and halogens) in the para-position of the phenyl ring of the parent compound 1, and compound 7 lacks the hydroxyl group of amino alcohol 1. In radioligand binding assays using recombinant human A(1), A(2A), A(2B), and A(3) receptors, all compounds showed very low or negligible affinity for A(1) and A(2B) receptors but compounds 3, 5, and 7 displayed a remarkably potent affinity for the A2A receptor with K-i values of 1-5 nM. Bromo derivative 3 displayed a selectivity A(1)/A(2A) = 62 and A(3)/A(2A) = 16 whereas the presence of a hydroxyl group (compound 5) improved the selectivity of A(1)/A(2A) and A(3)/A(2A) to 120- and 28-fold, respectively. When the methoxy derivative 4 lacks the hydroxyl group on the side chain (compound 7), the binding affinity for A(2A) is increased to 1 nM, improving selectivity ratios to 356- and 100-fold against A(1) and A(3), respectively. In Chinese hamster ovary cells transfected with human A2A and A(2B) receptors, most compounds showed a remarkable activity for the A2A receptor, except chloro derivative 2, with EC50 values ranging from 1.4 to 8.8 nM. The compounds behaved as good A(2A) agonists, and all were more selective than 5'-(N-ethylearboxamino)adenosine (NECA), with A(2B)/A(2A) ratios of cAMP accumulation ranging from 48 for compound 2 to 666 for compound 7 while the corresponding A(2B)/A(2A) ratio for NECA was only 9. Compounds 1, 3, 5, and 7 also displayed higher selectivities than NECA up to 100-fold in isolated aortas of rat and guinea pig. In guinea pig tracheal rings precontracted by carbachol, compounds 2 and 4 were more potent than adenosine (100-fold) and NECA (10-fold), whereas compounds 1 and 7 displayed similar effects to NECA. Pretreatment of the tracheal rings with A(2), A(2A), and A(2B) receptor antagonists 3,7-dimethyl-L-propargylxanthine, 8-(3-chlorostyryl)caffeine, and alloxazine produced a marked inhibition of the tracheal relaxations induced by compounds 1, 2, and 4, but none of the compounds showed selectivity toward any of the adenosine receptors.