Our previous work discovered that combining the appropriate 5′- and N⁶-substitution in adenosine derivatives leads to the highly selective human A₁ adenosine receptor (hA₁AR) agonists or highly potent dual hA₁AR agonists and hA₃AR antagonists. In order to explore novel dual adenosine receptor ligands, a series of N⁶-substituted-5′-pyrazolyl-adenosine and 2-chloro-adenosine derivatives were synthesized and assayed in vitro at all ARs. The N⁶-(±)-endo-norbornyl derivative 12 was the most potent and selective at A₁AR and effective as an analgesic in formalin test in mice, but none of the 5′-pyrazolyl series compounds showed a dual behavior at hA₁ and hA₃AR. Molecular modeling studies rationalized the structure–activity relationships and the selectivity profiles of the new series of A₁AR agonists. Interestingly, an unexpected inverted binding mode of the N⁶-tetrahydrofuranyl derivative 14 was hypothesized to explain its low affinity at A₁AR.

中文翻译：

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选择性A ₁腺苷受体激动剂的基于结构的设计，合成和体内抗伤害作用

我们以前的工作发现，在腺苷衍生物中结合适当的5'-和N ^6-取代可导致高度选择性的人A ₁腺苷受体（hA ₁ AR）激动剂或高效的双重hA ₁ AR激动剂和hA ₃ AR拮抗剂。为了探索新颖的双腺苷受体配体，合成了一系列N ^6-取代的5'-吡唑基-腺苷和2-氯-腺苷衍生物，并在所有AR中体外测定。所述Ñ ⁶ - （±） -内型-norbornyl衍生物12是最有效的和选择性A处₁AR在福尔马林试验中可作为镇痛药有效，但5'-吡唑基系列化合物均未在hA ₁和hA ₃ AR处表现出双重行为。分子建模研究合理化了一系列新的A ₁ AR激动剂的结构-活性关系和选择性。有趣的是，假设了N ^6-四氢呋喃基衍生物14的意外的反向结合模式，以解释其对A ₁ AR的低亲和力。