We expanded on a series of pyrido[2,1-f]purine-2,4-dione derivatives as human adenosine A₃ receptor (hA₃R) antagonists to determine their kinetic profiles and affinities. Many compounds showed high affinities and a diverse range of kinetic profiles. We found hA₃R antagonists with very short residence time (RT) at the receptor (2.2 min for 5) and much longer RTs (e.g., 376 min for 27 or 391 min for 31). Two representative antagonists (5 and 27) were tested in [³⁵S]GTPγS binding assays, and their RTs appeared correlated to their (in)surmountable antagonism. From a k_on–k_off–K_D kinetic map, we divided the antagonists into three subgroups, providing a possible direction for the further development of hA₃R antagonists. Additionally, we performed a computational modeling study that sheds light on the crucial receptor interactions, dictating the compounds’ binding kinetics. Knowledge of target binding kinetics appears useful for developing and triaging new hA₃R antagonists in the early phase of drug discovery.

中文翻译：

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作为人腺苷A ₃受体拮抗剂的吡啶并[2,1 - f ]嘌呤-2,4-二酮衍生物的结构亲和关系和结构动力学关系。

我们扩展了一系列作为人腺苷A ₃受体（hA ₃ R）拮抗剂的吡啶并[2,1 - f ]嘌呤-2,4-二酮衍生物，以确定它们的动力学特征和亲和力。许多化合物显示出高亲和力和多种动力学曲线。我们发现hA ₃ R拮抗剂在受体上的停留时间（RT）非常短（5分钟为2.2分钟），而RT则更长（例如376分钟为27分钟或391分钟为31分钟）。在[ ³⁵ S]GTPγS结合试验中测试了两个代表性的拮抗剂（5和27），它们的RT似乎与其（不可克服的）拮抗作用相关。从k_在– k _off – K _D动力学图中，我们将拮抗剂分为三个亚组，为进一步开发hA ₃ R拮抗剂提供了可能的方向。此外，我们进行了计算建模研究，阐明了关键的受体相互作用，决定了化合物的结合动力学。在药物发现的早期阶段，靶结合动力学的知识似乎对开发和分类新的hA ₃ R拮抗剂很有用。