Discovery and Development of S6821 and S7958 as Potent TAS2R8 Antagonists

Fotsing, Joseph R.; Darmohusodo, Vincent; Patron, A. P.; Ching, Brett; Brady, Thomas P.; Arellano, Melissa; Chen, Qing; Davis, Timothy J.; Liu, Hanghui; Servant, Guy; Zhang, Lan; Williams, Mark E.; Saganich, Michael; Ditschun, Tanya L.; Tachdjian, Catherine; Karanewsky, Donald S.

doi:10.1021/acs.jmedchem.0c00388

Cited by 14 publications

(8 citation statements)

References 83 publications

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“…The results showed that TAS2R1, 8, and 41 receptors were activated by chloramphenicol [1 mM] 43 , 55 – 57 ; TAS2R3 and 7 were activated by chloroquine [10 mM] 58 ; TAS2R4 was activated by the Trp-Trp-Trp peptide 59 ; TAS2R5 was activated by 1,10-phenanthroline [1 mM] 60 ; TAS2R9 was activated by procainamide [20 mM] 61 ; TAS2R10 was activated by cucurbitacin E [30 µM] 41 ; TAS2R13 was activated by oxyphenonium [10 mM] 62 ; TAS2R14 was activated by flufenamic acid [0.3 mM] 56 ; TAS2R16 was activated by salicin [10 mM] 63 ; TAS2R38 was activated by PROP [1 mM] 64 ; TAS2R39 was activated by ranitidine [10 mM] 62 , 65 ; TAS2R40 was activated by humulone [30 µM] 66 ; TAS2R43, and TAS2R31 were activated by aristolochic acid [30 µM] 40 ; TAS2R46 was activated by strychnine [300 µM] 41 ; TAS2R30 was activated by denatonium [300 µM] 56 ; TAS2R20 was activated by cromolyn [10 mM] 56 ; and TAS2R50 was activated by andrographolide [1 mM] 67 . In contrast, the negative controls, which the TAS2Rs were replaced by the empty vector, lacked responses to these bitter compounds (Fig.…”

Section: Resultsmentioning

confidence: 99%

Activation of specific bitter taste receptors by olive oil phenolics and secoiridoids

Cui

Chen

et al. 2021

Sci Rep

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Extra-virgin olive oil (EVOO) is a critical component of the Mediterranean diet, which has been found beneficial to human health. Bitterness is often positively associated with the presence of phenolic compounds in EVOO. There are twenty-five bitter taste receptors (TAS2Rs) in humans, each of which responds to specific bitter tastants. The identity of phenolic compounds and the bitter taste receptors they stimulate remain unknown. In this study, we isolated 12 phenolic and secoiridoid compounds from the olive fruit and the oil extracted from it, and tested their ability to stimulate bitter taste receptor activity, using a calcium mobilization functional assay. Our results showed that seven out of twelve studied compounds activated TAS2R8, and five of them activated TAS2R1, TAS2R8, and TAS2R14. The phenolic compounds oleuropein aglycon and ligstroside aglycon were the most potent bitter tastants in olive oil. TAS2R1 and TAS2R8 were the major bitter taste receptors activated most potently by these phenolic compounds. The results obtained here could be utilized to predict and control the bitterness of olive oil based on the concentration of specific bitter phenolics produced during the milling process of olives.

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Section: Resultsmentioning

confidence: 99%

Activation of specific bitter taste receptors by olive oil phenolics and secoiridoids

Cui

Chen

et al. 2021

Sci Rep

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“…Bitterness may be reduced or blocked at any stage of processing, including in the brain (Coupland and Hayes, 2014; Fotsing et al, 2020; Slack et al, 2010). Sweet taste, for example, is believed to act at least in part by inhibiting bitter signals in the brain (Kroeze and Bartoshuk, 1985).…”

Section: Resultsmentioning

confidence: 99%

Sophorolipid Reduces Bitter Taste in Humans In Vivo and In Vitro

Özdener

Spielman

Wise

2021

J Surfact & Detergents

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Bitter taste warns us against ingesting toxic chemicals but can also discourage consumption of healthful nutrients and prescribed medications. Thus, discovery of ingredients to reduce bitterness is an important research priority. The potential bitter‐taste‐blocking effect of sophorolipids has recently been reported. Sophorolipids are biosurfactant glycolipids normally synthesized via yeast fermentation. In the current experiments, the effect of sophorolipid on bitter taste was evaluated using both cultured human taste papillae (HBO) cells and in vivo sensory experiments with human tasters. Sophorolipids significantly reduced responses of HBO cells to a mixture of diverse bitter compounds. Human participants rated the bitterness of a mixture of diverse bitter compounds as less intensely bitter both after prerinsing with a sophorolipid solution and when sophorolipids were added to the mixture. Taken together, these results suggest that sophorolipids may reduce perceived bitterness in humans, at least in part by acting on peripheral mechanisms. Although further work is needed to confirm these findings and determine the exact mechanism(s) of action, thus far sophorolipids show promise as candidate ingredients to reduce bitterness.

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“…In a recent study, synthetic TAS2R8 inhibitors that functioned as potent bitter taste blockers have been identified and optimized through using a combination of a stable TAS2R8 cell line for fluorescence-based screening assay and human sensory evaluation 32 . Therefore, our bioluminescence-based assay will serve as a valuable tool as a screening assay to discover TAS2R inhibitors, followed by validation of bitter taste blockers in human test panels.…”

Section: Discussionmentioning

confidence: 99%

Construction of a bioluminescence-based assay for bitter taste receptors (TAS2Rs)

Tan

Seetoh²

2022

Sci Rep

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In humans, a family of 25 bitter taste receptors (TAS2Rs) mediates bitter taste perception. A common approach to characterize bitter causative agents involves expressing TAS2Rs and the appropriate signal transducers in heterologous cell systems, and monitoring changes in the intracellular free calcium levels upon ligand exposure using a fluorescence-based modality, which typically suffers from a low signal window, and is susceptible to interference by autofluorescence, therefore prohibiting its application to screening of plant or food extracts, which are likely to contain autofluorescent compounds. The aim of this study is to develop and validate a bioluminescence-based intracellular calcium release assay for TAS2Rs that has a better assay performance than a fluorescence-based assay. Furthermore, the bioluminescence-based assay enabled the evaluation of TAS2R agonists within an autofluorescent matrix, highlighting its potential utility in the assessment of the bitterness-inducing properties of plant or food fractions by the food industry. Additionally, improvement to the bioluminescence-based assay for some TAS2Rs was achieved by altering their N-terminal signal sequences, leading to signal window enhancement. Altogether, the bioluminescence-based TAS2R assay can be used to perform functional studies of TAS2Rs, evaluate TAS2R-modulating properties of autofluorescent samples, and facilitate the discovery of compounds that can function as promising bitter taste modulators.

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Discovery and Development of S6821 and S7958 as Potent TAS2R8 Antagonists

Cited by 14 publications

References 83 publications

Activation of specific bitter taste receptors by olive oil phenolics and secoiridoids

Activation of specific bitter taste receptors by olive oil phenolics and secoiridoids

Sophorolipid Reduces Bitter Taste in Humans In Vivo and In Vitro

Construction of a bioluminescence-based assay for bitter taste receptors (TAS2Rs)

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