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首页> 外文期刊>Bioorganic and medicinal chemistry >Synthesis and pharmacological characterization of a new series of 5,7-disubstituted-(1,2,4)triazolo(1,5-a)(1,3,5)triazine derivatives as adenosine receptor antagonists: A preliminary inspection of ligand-receptor recognition process.
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Synthesis and pharmacological characterization of a new series of 5,7-disubstituted-(1,2,4)triazolo(1,5-a)(1,3,5)triazine derivatives as adenosine receptor antagonists: A preliminary inspection of ligand-receptor recognition process.

机译：一系列新的5,7-二取代-（1,2,4）三唑并（1,5-a）（1,3,5）三嗪衍生物作为腺苷受体拮抗剂的合成和药理学表征：配体-受体识别过程。

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摘要

A new series of triazolotriazines variously substituted at the C5 and N7 (5-25) positions was synthesized and fully characterized at the four adenosine receptor (AR) subtypes. In particular, arylacetyl or arylcarbamoyl moieties were introduced at the N7 position, which enhanced affinity at the hA(2B) and hA(3) ARs, respectively, when utilized on the pyrazolo-triazolopyrimidine nucleus as we reported in the past. In general, compounds with a free amino group at the 7 position (5, 6), showed good affinity at the rat (r) A(2A) AR (range 18.3-96.5nM), while the introduction of a phenylcarbamoyl moiety at the N7 position (12, 19, 24) slightly increased the affinity at the hA(3) AR (range 311-633nM) with respect to the unsubstituted derivatives. The binding profiles of the synthesized analogues seemed to correlate with the substitutions at the C5 and N7 positions. At the hA(2B) AR, derivative 5, which contained a free amino group at the 7 position, was the most potent (EC(50) 3.42microM) and could represent a starting point for searching new non-xanthine hA(2B) AR antagonists. Molecular models of the rA(2A) and hA(3) ARs were constructed by homology to the recently reported crystallographic structure of the hA(2A) AR. A preliminary receptor-driven structure-activity relationship (SAR) based on the analysis of antagonist docking has been provided.
机译：合成了一系列在C5和N7（5-25）位置上不同取代的三唑并三嗪，并在四个腺苷受体（AR）亚型上进行了全面表征。特别是，如我们过去报道的那样，当在吡唑并三唑并嘧啶核上使用时，在N7位置引入了芳基乙酰基或芳基氨基甲酰基部分，分别增强了在hA（2B）和hA（3）AR上的亲和力。通常，在7位（5、6）处具有游离氨基的化合物在大鼠（r）A（2A）AR（范围18.3-96.5nM）处显示出良好的亲和力，而在（r）A（2A）AR处引入了苯基氨基甲酰基部分N7位置（12、19、24）相对于未取代衍生物略微增加了hA（3）AR（范围311-633nM）的亲和力。合成类似物的结合谱似乎与C5和N7位的取代相关。在hA（2B）AR处，衍生物5最有效（EC（50）3.42microM），可能代表寻找新的非黄嘌呤hA（2B）的起点，该衍生物在7位上含有一个游离氨基。 AR拮抗剂。 rA（2A）和hA（3）AR的分子模型是通过与最近报道的hA（2A）AR的晶体结构同源而构建的。提供了基于拮抗剂对接分析的初步受体驱动的结构-活性关系（SAR）。

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