Lactisole

Lactisole is a canonical antagonist of sweet taste receptor, selectively targeting to T1R3 subunit^[1]. T1R3 is a common key subunit of the sweet taste receptor (hT1R2/hT1R3) and the umami taste receptor (hT1R1/hT1R3), responsible for recognizing sugars, artificial sweeteners and L-amino acids, thereby triggering taste signaling pathways^[2]. Lactisole blocks the activation of natural sweeteners by binding to the transmembrane domain of the receptor through a non-competitive allosteric mechanism and is commonly used in taste physiology and food science research^[3-5].

In vitro, treatment of MIN6 cells with Lactisole(5-10mM; 1h) dose-dependently inhibits insulin secretion induced by sweeteners (acesulfame-K, sucralose, glycyrrhizin) and glucose (IC₅₀=4mM), reduces intracellular [NADH] and [ATP] levels, attenuates Ca²⁺ elevation induced by these sweeteners and glucose, but does not affect cAMP elevation^[6].

In vivo, co-administration of Lactisole (30mg/kg/day; i.g.; 12 weeks) and Alzheimer’s disease (AD) drug Sodium oligomannate (GV-971) attenuated the effects of GV-971 on serum serotonin and CCK levels, vagal afferent firing, and cognitive behaviors^[7]. Oral administration of streptozotocin-induced diabetic male rats with Lactisole(10mg/kg; 2h) negates the beneficial effects of duodenal–jejunal bypass (DJB) surgeries on glucose tolerance by inhibiting GLP-1 and GLP-2 secretion, reducing intestinal villus height and crypt depth, and modulating the expression of taste receptors and glucose transporters^[8].

References:
[1] Schiffman SS, Booth BJ, Sattely-Miller EA, Graham BG, Gibes KM. Selective inhibition of sweetness by the sodium salt of +/-2-(4-methoxyphenoxy)propanoic acid. Chem Senses. 1999;24(4):439-447.
[2] Kojima I, Nakagawa Y, Hamano K, Medina J, Li L, Nagasawa M. Glucose-Sensing Receptor T1R3: A New Signaling Receptor Activated by Glucose in Pancreatic β-Cells. Biol Pharm Bull. 2015;38(5):674-679.
[3] Jiang P, Cui M, Zhao B, et al. Lactisole interacts with the transmembrane domains of human T1R3 to inhibit sweet taste. J Biol Chem. 2005;280(15):15238-15246.
[4] Johnson C, Birch GG, MacDougall DB. The effect of the sweetness inhibitor 2(-4-methoxyphenoxy)propanoic acid (sodium salt) (Na-PMP) on the taste of bitter-sweet stimuli. Chem Senses. 1994;19(4):349-358.
[5] Schweiger K, Grüneis V, Treml J, et al. Sweet Taste Antagonist Lactisole Administered in Combination with Sucrose, But Not Glucose, Increases Energy Intake and Decreases Peripheral Serotonin in Male Subjects. Nutrients. 2020;12(10):3133.
[6] Hamano K, Nakagawa Y, Ohtsu Y, et al. Lactisole inhibits the glucose-sensing receptor T1R3 expressed in mouse pancreatic β-cells. J Endocrinol. 2015;226(1):57-66.
[7] Gong HS, Pan JP, Guo F, et al. Sodium oligomannate activates the enteroendocrine-vagal afferent pathways in APP/PS1 mice. Acta Pharmacol Sin. 2024;45(9):1821-1831.
[8] Sun S, Wang A, Kou R, et al. Duodenal-Jejunal Bypass Restores Sweet Taste Receptor-Mediated Glucose Sensing and Absorption in Diabetic Rats. J Diabetes Res. 2024;2024:5544296.

Lactisole是一种经典的甜味受体拮抗剂，选择性地靶向T1R3亚基^[1]。T1R3是甜味受体（hT1R2/hT1R3）和鲜味受体（hT1R1/hT1R3）的共同关键亚基，负责识别糖、人工甜味剂和L-氨基酸，从而触发味觉信号通路^[2]。Lactisole通过结合受体的跨膜结构域，以非竞争性变构机制阻断天然甜味剂的激活，常用于味觉生理学和食品科学研究^[3-5]。

在体外实验中，Lactisole（5-10mM；1h）处理MIN6细胞，剂量依赖性地抑制由甜味剂（阿斯巴甜-K、三氯蔗糖、甘草甜素）和葡萄糖诱导的胰岛素分泌（IC₅₀=4mM），降低细胞内[NADH]和[ATP]水平，减弱这些甜味剂和葡萄糖诱导的细胞内Ca²⁺升高，但不影响cAMP升高^[6]。

在体内实验中，Lactisole（30mg/kg/天；灌胃；12周）与阿尔茨海默病（AD）药物甘露寡糖二酸（GV-971）联合使用，减弱了GV-971对血清5-羟色胺和胆囊收缩素（CCK）水平、迷走神经传入放电以及认知行为的影响^[7]。在链脲佐菌素诱导的糖尿病雄性大鼠中，口服Lactisole（10mg/kg; 2h）通过抑制GLP-1和 GLP-2分泌、降低肠绒毛高度和隐窝深度以及调节味觉受体和葡萄糖转运蛋白的表达，抵消了十二指肠 - 空肠旁路（DJB）手术对葡萄糖耐受性改善的有益作用^[8]。