GIV3727
compound / compound-giv3727
/ 4-(2,2,3-trimethylcyclopentyl)butanoic acid
GIV3727 is a small-molecule human bitter taste receptor antagonist identified by high-throughput screening; the first hTAS2R antagonist reported to have in vivo efficacy.
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Reading the bitterness
GIV3727 is a small molecule identified by high-throughput screening that acts as an antagonist for specific human bitter taste receptors. It is considered the first human bitter taste receptor antagonist whose efficacy was confirmed in in vivo studies. It was found among approximately 17,854 compounds screened against the bitter taste receptor TAS2R31 and was one of 139 candidate antagonists. GIV3727 inhibited this receptor at IC50 concentrations of 6.4±2.4 micromoles against the artificial sweetener acesulfame K and 7.9±6.1 micromoles against saccharin.
Among the 25 human bitter taste receptor subtypes tested, examination of 18 showed that GIV3727 inhibited 6 receptors including TAS2R31, while the remainder were not inhibited (however, for TAS2R7, an exact EC90 agonist concentration could not be established, and whether true EC90 inhibition occurred is considered uncertain). This inhibition was reversible, returning to baseline when the culture medium was washed away. In experiments using receptor mutants based on the TAS2R46 scaffold, a basic amino acid residue at position 7.39 was identified as an important contact point involved in sensitivity to GIV3727. However, another receptor possessing the same residue (TAS2R50) did not exhibit sensitivity, so this residue alone does not determine sensitivity.
Human taste tests also confirmed that this receptor antagonism reduces bitterness. In a 2-choice test using a 2 mM solution of acesulfame K, 95% of the panel chose the solution with 30 ppm (150 micromoles) GIV3727 added as 「より苦くない」 (in translation: "less bitter"), and bitterness intensity was rated as having decreased from moderate to barely perceptible. Sweetness showed no marked effect; only 55% reported it as sweeter than the control, and no difference was observed in sweetness intensity ratings. The same directional effect was confirmed with 3 mM saccharin.
However, the completeness of receptor inhibition at the cellular level did not necessarily correspond to the actual reduction in bitterness perceived by humans. Not all panelists reported complete elimination of bitterness; the authors proposed 3 hypotheses: possible constraints on the pathway by which this compound reaches receptors in the mouth, possible inter-individual genetic variation in TAS2R43 or TAS2R31, and the possibility that the sweetener itself evokes both sweet and bitter sensations, making discrimination difficult. None of these were tested in this paper itself.
Sources for this overview
Modulation of bitter taste perception by a small molecule hTAS2R antagonist
Checked for this overview: Screening of 17,854 compounds and 139 candidate antagonists; confirmation of receptor inhibition by IC50 values / Testing of 18 of the 25 types and inhibition of 6 receptors; confirmation of contact points in mutant experiments / 95% selection in 2-choice test and confirmation of reduced bitterness intensity; confirmation of no effect on sweetness / Confirmation of discrepancy between cellular experiments and human ratings, and the 3 hypotheses proposed by the authors
Follow the connections
GIV3727 →antagonizes→ TAS2R31
Structured claims — open a section to read each claim's confidence, evidence and limits
Sensory (1)
Scope: A human 2-alternative forced-choice test with anchored line-scale intensity ratings. Aqueous sweetener solutions, not a pharmaceutical product.
Note: Sweetness was unaffected (55% selected the control as sweeter, with no significant difference in ratings), and 30 ppm GIV3727 in water could not be distinguished from water in a triangle test (n = 50, p = 0.196). The effect is therefore specific to bitterness.
Show data
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). Rated bitterness intensity fell from moderate to merely recognizable."Mechanism and receptors (1)
Scope: Calcium imaging in HEK293 cells stably or transiently expressing a single hTAS2R together with the chimeric G protein G16gust44. The panel screen tested antagonists at 25 uM
Note: Identified from a screen of 17,854 compounds, which yielded 139 candidate antagonists. The authors conclude it is most likely an orthosteric, non-surmountable antagonist: 25 uM GIV3727 shifted the agonist EC50 by 3- to 10-fold and reduced the maximal signal amplitude by 35-70%.
Show data
compound-giv3727 —antagonizes→ receptor-tas2r31