A sweet taste receptor is composed of heterodimeric G-protein-coupled receptors T1R2 and T1R3. Although there are many sweet tastants, only a few compounds have been reported as negative allosteric modulators (NAMs), such as lactisole, its structural derivative 2,4-DP, and gymnemic acid. In this study, candidates for NAMs of the sweet taste receptor were explored, focusing on the structural motif of lactisole. Ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), has an α-methylacetic acid moiety, and this structure is also shared by lactisole and 2,4-DP. When ibuprofen was applied together with 1 mM aspartame to the cells that stably expressed the sweet taste receptor, it inhibited the receptor activity in a dose-dependent manner. The IC₅₀ value of ibuprofen against the human sweet taste receptor was calculated as approximately 12 μM, and it was almost equal to that of 2,4-DP, which is known as the most potent NAM for the receptor to date. On the other hand, when the inhibitory activities of other profens were examined, naproxen also showed relatively potent NAM activity against the receptor. The results from both mutant analysis for the transmembrane domain (TMD) of T1R3 and docking simulation strongly suggest that ibuprofen and naproxen interact with T1R3-TMD, similar to lactisole and 2,4-DP. However, although 2,4-DP and ibuprofen had almost the same inhibitory activities, these activities were acquired by filling different spaces of the ligand pocket of T1R3-TMD; this knowledge could lead to the rational design of a novel NAM against the sweet taste receptor.

中文翻译：

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布洛芬是一种非甾体类抗炎药，是人类甜味受体的有效抑制剂。

甜味受体由异二聚体G蛋白偶联受体T1R2和T1R3组成。尽管有很多甜味剂，但只有少数化合物被报道为负变构调节剂（NAM），例如乳臭素，其结构衍生物2,4-DP和裸草酸。在这项研究中，探索了甜味受体NAM的候选者，重点放在了乳臭素的结构基序上。布洛芬是一种非甾体类抗炎药（NSAID），具有α-甲基乙酸部分，并且该结构也被乳糖苷和2,4-DP所共有。当布洛芬与1 mM阿斯巴甜一起应用于稳定表达甜味受体的细胞时，它以剂量依赖的方式抑制受体的活性。IC ₅₀布洛芬抗人甜味受体的最大值约为12μM，几乎等于2,4-DP的值，这是迄今为止已知最强的NAM受体。另一方面，当检查其他profens的抑制活性时，萘普生也显示出相对强效的针对受体的NAM活性。来自T1R3跨膜结构域（TMD）的突变体分析和对接模拟的结果都强烈表明，布洛芬和萘普生与T1R3-TMD相互作用，类似于lactisole和2,4-DP。然而，尽管2，4-DP和布洛芬具有几乎相同的抑制活性，但这些活性是通过填充T1R3-TMD的配体口袋的不同空间而获得的。这些知识可能会导致针对甜味受体的新型NAM的合理设计。