P‐glycoprotein (P‐gp) is an ATP‐dependent efflux pump that has a marked impact on the absorption, distribution, and excretion of therapeutic drugs. As P‐gp inhibition can result in drug–drug interactions and altered drug bioavailability, identifying molecular properties that are linked to inhibition is of great interest in drug development. In this study, we combined chemical synthesis, in vitro testing, quantitative structure–activity relationship analysis, and docking studies to investigate the role of hydrogen bond (H‐bond) donor/acceptor properties in transporter–ligand interaction. In a previous work, it has been shown that propafenone analogs with a 4‐hydroxy‐4‐piperidine moiety exhibit a generally 10‐fold higher P‐gp inhibitory activity than expected based on their lipophilicity. Here, we specifically expanded the data set by introducing substituents at position 4 of the 4‐phenylpiperidine moiety to assess the importance of H‐bond donor/acceptor features in this region. The results suggest that indeed an H‐bond acceptor, such as hydroxy and methoxy, increases the affinity by forming a H‐bond with Tyr310.

中文翻译：

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具有额外 H 键受体基团的普罗帕酮类似物显示对 P-糖蛋白的抑制活性增加

P-糖蛋白 (P-gp) 是一种依赖 ATP 的外排泵，对治疗药物的吸收、分布和排泄具有显着影响。由于 P-gp 抑制可导致药物-药物相互作用和改变药物生物利用度，因此识别与抑制相关的分子特性在药物开发中具有重要意义。在这项研究中，我们结合化学合成、体外测试、定量构效关系分析和对接研究来研究氢键 (H-bond) 供体/受体特性在转运蛋白-配体相互作用中的作用。在之前的工作中，已经表明具有 4-羟基-4-哌啶部分的普罗帕酮类似物的 P-gp 抑制活性通常比基于其亲脂性预期的高 10 倍。这里，我们通过在 4-苯基哌啶部分的第 4 位引入取代基来扩展数据集，以评估 H 键供体/受体特征在该区域的重要性。结果表明，确实有一个氢键受体，如羟基和甲氧基，通过与 Tyr310 形成氢键来增加亲和力。