Small-molecule human bitter taste receptor antagonist identified by high-throughput screening; first reported hTAS2R antagonist with in vivo efficacy.
GIV3727は2 mM acesulfame K and 3 mM saccharin solutions: 95% of panelists selected the sample containing 30 ppm (150 uM) GIV3727 as the least bitter (p < 0.001), with rated bitter intensity falling from moderate to merely recognizableの知覚苦味を低減する支持あり
範囲: Human 2-alternative forced choice trials with anchored line-scale intensity ratings; aqueous sweetener solutions, not a drug product
注記: Sweetness was unaffected (55% chose the control as sweeter; ratings not significantly different), and 30 ppm GIV3727 in water could not be discriminated from water in a triangle test (n = 50, p = 0.196), so the effect is specific to bitterness.
In 2-alternative forced choice trials with anchored line-scale ratings, 95% of the panel selected the 2 mM acesulfame K solution containing 30 ppm (150 uM) GIV3727 as the least bitter (p < 0.001) and rated bitterness as falling from moderate to merely recognizable. Sweetness was unaffected: only 55% chose the control as sweeter and sweet intensity ratings did not differ, and a GIV3727-containing 7% sucrose sample could not be discriminated from the sucrose reference. GIV3727 at 30 ppm in water could not be discriminated from water in a triangle test (n = 50, p = 0.196). The same direction of effect was obtained with 3 mM saccharin.
限界: Panel size for the 2-AFC bitterness trials is not stated in the text as read. The stimuli are sweeteners in water, not a medicinal product, so transfer to bitter APIs is untested here.
限定: The authors note that while GIV3727 abolished hTAS2R43/31 activation in vitro, not all panelists detected a complete reduction in bitterness in vivo and the intensity ratings show the bitterness was reduced but not fully abolished. They offer three candidate explanations: anatomical constraints limiting compound access in the mouth, non-synonymous SNPs or genomic deletions in TAS2R43/31 in a small number of individuals, and the fact that the sweeteners elicit both sweet and bitter sensations, which may hinder discrimination.
限界: The three explanations are hypotheses; none was tested in this paper. A receptor-level block does not translate into a perceptual-level block of the same magnitude.
データを表示
compound-giv3727 —reduces_perceived_bitterness_of→ "2 mM acesulfame K and 3 mM saccharin solutions: 95% of panelists selected the sample containing 30 ppm (150 uM) GIV3727 as the least bitter (p < 0.001), with rated bitter intensity falling from moderate to merely recognizable"claim: clm-giv3727-human-bitterness-reduction / type: sensory / 更新: 2026-08-30
範囲: Calcium imaging in HEK293 cells stably or transiently expressing single hTAS2Rs with the chimeric G-protein G16gust44; antagonist tested at 25 uM in the panel screen
注記: Identified from a 17,854-compound screen that yielded 139 candidate antagonists. Authors conclude it is likely an orthosteric, insurmountable antagonist: 25 uM GIV3727 shifted agonist EC50 3- to 10-fold and reduced maximal signal amplitude by 35-70%.
High-throughput calcium-imaging screening of 17,854 compounds against hTAS2R31 yielded 139 candidate antagonists, of which GIV3727 gave IC50 6.4 +/- 2.4 uM against acesulfame K and 7.9 +/- 6.1 uM against saccharin (n = 3). Inhibition was reversible on washout. Tested at 25 uM against 18 of the 25 hTAS2Rs with known agonists, GIV3727 significantly inhibited six receptors (hTAS2R4, 7, 40, 43, 31, 20) and not the remainder. Mutagenesis showed a basic residue at position 7.39 (Lys265) is a key contact point in the hTAS2R46 backbone.
限界: For four receptors (hTAS2R3/5/7/13) an accurate EC90 agonist concentration could not be established, so the maximal non-artifactual agonist concentration was used instead and hTAS2R7 inhibition at a true EC90 is therefore uncertain. Lysine at 7.39 is not sufficient for sensitivity, since hTAS2R50 also carries it but is insensitive.
データを表示
compound-giv3727 —antagonizes→ receptor-tas2r31claim: clm-giv3727-tas2r-antagonism / type: mechanism / 更新: 2026-08-30