Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, P.O. Box 9502, 2300 RA Leiden, the Netherlands.
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Biochem Pharmacol. 2022 Jun;200:115027. doi: 10.1016/j.bcp.2022.115027. Epub 2022 Apr 6.
A adenosine receptor (AAR) antagonists have therapeutic potential in inflammation-related diseases such as asthma, chronic obstructive pulmonary disease and cancer. However, no drug is currently clinically approved, creating a demand for research on novel antagonists. Over the last decade, the study of target binding kinetics, along with affinity and potency, has been proven valuable in early drug discovery stages, as it is associated with improved in vivo drug efficacy and safety. In this study, we report the synthesis and biological evaluation of a series of xanthine derivatives as AAR antagonists, including an isothiocyanate derivative designed to bind covalently to the receptor. All 28 final compounds were assessed in radioligand binding experiments, to evaluate their affinity and for those qualifying, kinetic binding parameters. Both structure-affinity and structure-kinetic relationships were derived, providing a clear relationship between affinity and dissociation rate constants. Two structurally similar compounds, 17 and 18, were further evaluated in a label-free assay due to their divergent kinetic profiles. An extended cellular response was associated with long AAR residence times. This link between a ligand's AAR residence time and its functional effect highlights the importance of binding kinetics as a selection parameter in the early stages of drug discovery.
腺嘌呤受体（AAR）拮抗剂在炎症相关疾病（如哮喘、慢性阻塞性肺疾病和癌症）中具有治疗潜力。然而，目前没有药物在临床上获得批准，这就需要研究新的拮抗剂。在过去的十年中，研究靶标结合动力学以及亲和力和效力已被证明在药物发现的早期阶段非常有价值，因为它与提高体内药物疗效和安全性有关。在这项研究中，我们报告了一系列黄嘌呤衍生物作为 AAR 拮抗剂的合成和生物学评价，包括设计与受体共价结合的异硫氰酸酯衍生物。所有 28 个最终化合物均在放射性配体结合实验中进行了评估，以评估它们的亲和力，并对那些合格的化合物进行了动力学结合参数评估。我们得出了结构-亲和力和结构-动力学关系，清楚地表明了亲和力和离解速率常数之间的关系。由于它们的动力学特征不同，结构相似的两种化合物 17 和 18 进一步在无标记测定中进行了评估。与 AAR 驻留时间较长相关的是细胞的扩展反应。配体与 AAR 的驻留时间与其功能效应之间的这种联系突出了结合动力学作为药物发现早期选择参数的重要性。
