Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan.
Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan.
Chem Senses. 2020 Nov 7;45(8):667-673. doi: 10.1093/chemse/bjaa057.
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.
甜味受体由异二聚体 G 蛋白偶联受体 T1R2 和 T1R3 组成。虽然有许多甜味剂，但只有少数化合物被报道为负变构调节剂 (NAM)，如乳酮、其结构衍生物 2,4-DP 和葫芦巴碱。在这项研究中，探索了甜味受体的 NAM 候选物，重点是乳酮的结构基序。布洛芬是一种非甾体抗炎药 (NSAID)，具有α-甲基乙酸部分，而乳酮和 2,4-DP 也具有这种结构。当布洛芬与 1mM 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活性。布洛芬对人甜味受体的 IC50 值约为 12μM，与迄今为止已知的最有效的受体 NAM 2,4-DP 几乎相等。另一方面，当检查其他非甾体抗炎药的抑制活性时，萘普生对受体也表现出相对较强的 NAM 活性。T1R3 跨膜域 (TMD) 的突变分析和对接模拟的结果强烈表明，布洛芬和萘普生与 T1R3-TMD 相互作用，类似于乳酮和 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 配体口袋的不同空间获得的；这一知识可以导致针对甜味受体的新型 NAM 的合理设计。
