Examining the Role of the Linker in Bitopic N6‑Substituted Adenosine Derivatives Acting as Biased Adenosine A1 Receptor Agonists

The adenosine A1 receptor is a therapeutic target based on its ability to provide cardioprotection during episodes of myocardial ischemia and reperfusion injury. However, the clinical translation of A1R agonists has been hindered by dose-limiting adverse effects (bradycardia and hypotension). Previously, we demonstrated that the bitopic agonist VCP746 (1), consisting of an adenosine pharmacophore linked to an allosteric moiety, can stimulate cardioprotective A1R signaling effects in the absence of unwanted bradycardia. This study maps the structure–activity relationships of 1 through modifications to the linker moiety. Derivatives differing in the flexibility, length, and nature of the linker were assessed, which revealed that the linker is tolerant of several modifications including added rigidity. Ligands featuring 1,4-disubstituted 1,2,3-triazoles were the most biased of the novel analogues but also displayed sub-nanomolar potency in a cAMP accumulation assay at the A2BR. To our knowledge, 10 is the most potent A2BR agonist published to date.腺苷A1受体（adenosine A1 receptor）是一类治疗靶点，因其在心肌缺血再灌注损伤发作期间可发挥心脏保护作用。然而，A1R激动剂的临床转化一直受限于剂量限制性不良反应，即心动过缓与低血压。此前本研究团队已证实，双位配体激动剂VCP746（1）——由连接有变构基团的腺苷药效团构成——可在不引发不良心动过缓的前提下，介导具有心脏保护作用的A1R信号通路激活。本研究通过对其连接子基团进行结构修饰，阐明了化合物1的构效关系。研究人员对连接子的柔性、长度及性质存在差异的衍生物进行了活性评估，结果显示连接子可耐受多种修饰，包括引入刚性结构。其中带有1,4-二取代1,2,3-三唑结构的配体，在新型类似物中展现出最优的信号通路偏向性，同时在针对A2B受体（A2BR）的环磷酸腺苷（cAMP）积累实验中表现出亚纳摩尔级的活性。据本团队所知，化合物10是目前已发表的活性最强的A2BR激动剂。