A respected number of drugs suffer from bitter taste which results in patient incompliance. With the aim of solving the bitterness of guaifenesin, dimethyl maleate, maleate, glutarate, succinate, and dimethyl succinate prodrugs were designed and synthesized. Molecular orbital methods were utilized for the design of the ester prodrugs. The density functional theory (DFT) calculations revealed that the hydrolysis efficiency of the synthesized prodrugs is significantly sensitive to the pattern of substitution on C=C bond and distance between the nucleophile and the electrophile. The hydrolysis of the prodrugs was largely affected by the pH of the medium. The experimental t1/2 for the hydrolysis of guaifenesin dimaleate ester prodrugs in 1N HCl was the least and for guaifenesin dimethyl succinate was the highest. Functional heterologous expression of TAS2R14, a broadly tuned bitter taste receptor responding to guaifenesin, and experiments using these prodrugs revealed that, while some of the prodrugs still activated the receptor similarly or even stronger than the parent substance, succinate derivatization resulted in the complete loss of receptor responses. The predicted binding modes of guaifenesin and its prodrugs to the TAS2R14 homology model suggest that the decreased activity of the succinate derivatives may be caused by a clash with Phe247.

中文翻译：

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无苦愈创甘油醚前体药物的设计，合成，表征，体外动力学和苦味研究。

大量的药物具有苦味，导致患者不依从。为了解决愈创甘油醚的苦味，设计并合成了马来酸二甲酯，马来酸酯，戊二酸，琥珀酸酯和琥珀酸二甲酯的前药。分子轨道方法被用于酯前药的设计。密度泛函理论（DFT）计算表明，合成前药的水解效率对C = C键上的取代方式以及亲核试剂与亲电试剂之间的距离非常敏感。前药的水解很大程度上受培养基pH值的影响。愈创甘油醚二马来酸酯前药在1N HCl中的水解实验t1 / 2最小，而愈创甘油醚琥珀酸二甲酯的实验t1 / 2最高。TAS2R14的功能性异源表达是一种对愈创甘油醚有反应的广泛调节的苦味受体，使用这些前药进行的实验表明，尽管某些前药仍与母体物质相似或什至更强地激活该受体，但琥珀酸衍生化导致其完全丧失受体反应。愈创甘油醚及其前体药物与TAS2R14同源性模型的预测结合模式表明，琥珀酸酯衍生物活性降低可能是由于与Phe247的冲突引起的。