Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), P.O. Box 9502, 2300 RA Leiden (The Netherlands).
ChemMedChem. 2014 Apr;9(4):752-61. doi: 10.1002/cmdc.201300474. Epub 2014 Mar 3.
Classical drug design and development rely mostly on affinity- or potency-driven structure-activity relationships (SAR). Thus far, a given compound's binding kinetics have been largely ignored, the importance of which is now being increasingly recognized. In the present study, we performed an extensive structure-kinetics relationship (SKR) study in addition to a traditional SAR analysis at the adenosine A2A receptor (A2A R). The ensemble of 24 A2A R compounds, all triazolotriazine derivatives resembling the prototypic antagonist ZM241385 (4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino)ethyl)phenol), displayed only minor differences in affinity, although they varied substantially in their dissociation rates from the receptor. We believe that such a combination of SKR and SAR analyses, as we have done with the A2A R, will have general importance for the superfamily of G protein-coupled receptors, as it can serve as a new strategy to tailor the interaction between ligand and receptor.
经典的药物设计和开发主要依赖于亲和力或效力驱动的结构-活性关系（SAR）。到目前为止，一个给定化合物的结合动力学在很大程度上被忽视了，而其重要性现在正越来越受到重视。在本研究中，我们除了在腺苷 A2A 受体（A2A R）进行传统的 SAR 分析外，还进行了广泛的结构动力学关系（SKR）研究。这组 24 个 A2A R 化合物都是三唑并三嗪衍生物，类似于原型拮抗剂 ZM241385（4-（2-（（7-氨基-2-（呋喃-2-基）-[1,2,4]三唑并[1,5-a][1,3,5]三嗪-5-基）氨基）乙基）苯酚），尽管它们与受体的解离速率有很大差异，但亲和力仅略有差异。我们相信，这种 SKR 和 SAR 分析的结合，就像我们在 A2A R 中所做的那样，对于 G 蛋白偶联受体超家族具有普遍的重要性，因为它可以作为一种新的策略来调整配体和受体之间的相互作用。
