2-alkynyl-8-aryladenines possessing an amide moiety:: Their synthesis and structure-activity relationships of effects on hepatic glucose production induced via agonism of the A2B adenosine receptor
2-alkynyl-8-aryladenines possessing an amide moiety:: Their synthesis and structure-activity relationships of effects on hepatic glucose production induced via agonism of the A2B adenosine receptor
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DOI：
10.1016/s0968-0896(01)00201-2
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发表时间：
2001-10-01
影响因子：
3.5
通讯作者：
Abe, S
中科院分区：
文献类型：
--
作者：
Harada, H;Asano, O;Abe, S
合成了一系列具有腺嘌呤9位酰胺基团的2-炔基-8-芳基腺嘌呤衍生物。这些类似物在原代培养的大鼠肝细胞中对n -乙基羧甲酸腺苷（NECA）诱导的葡萄糖产生的抑制活性进行了评估。苯甲酰胺衍生物15f的活性最强（IC50 = 0.017 PM），是相应的9-甲基衍生物的15倍(1)。化合物15f对人A（2B）受体的选择性分别为人A(1)和人A（2A）受体的72倍和5.2倍。构效关系（SAR）研究表明，腺嘌呤核心和酰胺部分之间以苯环形式固定的三碳连接体对a （2B）的拮抗剂活性和选择性都很重要。用稳定转染人a （2B）受体的中国仓鼠卵巢细胞进行大鼠肝细胞葡萄糖实验的IC50值与cAMP实验的IC50值具有良好的相关性（r(2) = 0.94）。A(1)和A（2A）亲和力与抑制neca诱导的葡萄糖产生的效力无关。这些结果有力地支持了我们之前的结论，即腺苷激动剂诱导的大鼠肝细胞中葡萄糖的产生是通过A（2B）受体介导的。2001爱思唯尔科学有限公司版权所有。
A series of 2-alkynyl-8-aryladenine derivatives bearing an amide moiety at the 9-position of adenine was synthesized. These analogues were evaluated for inhibitory activity on N-ethylcarboxamidoadenosine (NECA)-induced glucose production in primary cultured rat hepatocytes. The in-primary benzamide derivative 15f was the most potent compound (IC50 = 0.017 PM), being 15-fold more active than the corresponding 9-methyl derivative (1). Compound 15f showed 72- and 5.2-fold selectivity for human A(2B) receptor versus human A(1) and A(2A) receptors, respectively. Structure-activity relationship (SAR) studies of the synthesized compounds indicated that a three-carbon linker, fixed in the form of a benzene ring, between the adenine core and the amide moiety is important for both A(2B) antagonistic activity and selectivity, The IC50 values in rat hepatocyte glucose assay correlated well with the IC50 values in cAMP assay using Chinese hamster ovary cells stably transfected with human A(2B) receptors (r(2) = 0.94). The A(1) and A(2A) affinities showed no correlation with the potency to inhibit NECA-induced glucose production. These results strongly support our previous conclusion that adenosine agonist-induced hepatic glucose production in rat hepatocytes is mediated through the A(2B) receptor. (C) 2001 Elsevier Science Ltd. All rights reserved.