Amino Acid Derivatives as Bitter Taste Receptor (T2R) Blockers

Pydi, Sai Prasad; Sobotkiewicz, Tyler; Billakanti, Rohini; Bhullar, Rajinder P.; Loewen, Michèle C.; Chelikani, Prashen

doi:10.1074/jbc.m114.576975

Cited by 82 publications

(107 citation statements)

References 40 publications

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“…23,24) Inhibition of hTAS2Rs, especially hTAS2R14, would be one approach to reducing the bitterness of drugs. To date, only a few bitter inhibitors have been discovered that block bittersubstance-evoked hTAS2R activation, such as Sakuranetin for hTAS2R31, 25,26) 6-methoxyflavanones for hTAS2R39, 27,28) γ-aminobutyric acid (GABA), N α ,N α -bis(carboxymethyl)-L-lysine (BCML) 29) and abscisic acid 30) for hTAS2R4, and (R)-Citronellal for hTAS2R43 and hTAS2R46. 31) Batenburg et al identified several hTAS2R14 receptor antagonists from a screening of synthetic compounds; however, the nature of these compounds did not allow their effects to be validated in vivo before extensive safety evaluation.…”

Section: Discussionmentioning

confidence: 99%

The Utility of the Artificial Taste Sensor in Evaluating the Bitterness of Drugs: Correlation with Responses of Human TASTE2 Receptors (hTAS2Rs)

et al. 2018

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The purpose of this study was to examine the ability of the artificial taste sensor to evaluate the bitterness of drugs by comparing the responses of the taste sensor with documented responses of human TASTE2 receptors (hTAS2Rs). For this purpose 22 bitter compounds, used as ingredients of pharmaceutical medicines in Japan and known ligands of hTAS2Rs, were selected for testing. Their solutions (0.01, 0.03, 0.1 mM) were evaluated by five different taste sensors (AC0, AN0, BT0, C00, AE1). Correlations between physicochemical parameters of the compounds and the responses of the taste sensors and hTAS2Rs were evaluated. From taste sensor measurements, diphenidol, haloperidol, diphenhydramine, dextromethorphan and papaverine, all ligands of hTAS2R 10 and/or hTAS2R14, were predicted to express strong bitterness, surpassing that of quinine. Responses of taste sensors BT0 were found to be significantly correlated with responses of hTAS2R14. High log P values (≧2.73) and responses of hTAS2R14 were also significantly correlated (** p<0.01, chi-square test). In conclusion, taste sensor BT0 is highly sensitive to bitterness and correlates significantly with hTAS2R14, making it useful for evaluating the bitterness of hydrophobic compounds which respond to hTAS2R14 and their inhibitors.

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Section: Discussionmentioning

confidence: 99%

The Utility of the Artificial Taste Sensor in Evaluating the Bitterness of Drugs: Correlation with Responses of Human TASTE2 Receptors (hTAS2Rs)

et al. 2018

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“…The mutants were synthesized commercially (Genscript USA Inc, NJ, USA). All the genes were cloned into pcDNA3.1 and transiently co-expressed in HEK293T cells with the chimeric G-protein Gα16/44 using lipofectamine-2000, as described previously (11,29). Cells were propagated in DMEM-F12 media, at 37 °C under 5 % CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…Cells were propagated in DMEM-F12 media, at 37 °C under 5 % CO 2 . Flow cytometry studies for elucidating cell surface expression of the receptors were carried out using the anti-FLAG antibody, exactly as described recently (11) . Intracellular calcium mobilization assays.…”

Section: Methodsmentioning

confidence: 99%

Abscisic Acid Acts as a Blocker of the Bitter Taste G Protein-Coupled Receptor T2R4

et al. 2015

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Bitter taste receptors (T2Rs) belong to the G protein-coupled receptor superfamily. In humans, 25 T2Rs mediate bitter taste sensation. In addition to the oral cavity, T2Rs are expressed in many extraoral tissues, including the central nervous system, respiratory system, and reproductive system. To understand the mechanistic roles of the T2Rs in oral and extraoral tissues, novel blockers or antagonists are urgently needed. Recently, we elucidated the binding pocket of T2R4 for its agonist quinine, and an antagonist and inhibitory neurotransmitter, γ-aminobutyric acid. This structure-function information about T2R4 led us to screen the plant hormone abscisic acid (ABA), its precursor (xanthoxin), and catabolite phaseic acid for their ability to bind and activate or inhibit T2R4. Molecular docking studies followed by functional assays involving calcium imaging confirmed that ABA is an antagonist with an IC50 value of 34.4 ± 1.1 μM. However, ABA precursor xanthoxin acts as an agonist on T2R4. Interestingly, molecular model-guided site-directed mutagenesis suggests that the T2R4 residues involved in quinine binding are also predominantly involved in binding to the novel antagonist, ABA. The antagonist ability of ABA was tested using another T2R4 agonist, yohimbine. Our results suggest that ABA does not inhibit yohimbine-induced T2R4 activity. The discovery of natural bitter blockers has immense nutraceutical and physiological significance and will help in dissecting the T2R molecular pathways in various tissues.

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“…Other compounds (such as the endogenous γ-aminobutyric acid or Nα,Nα-bis(carboxymethyl)-L-lysine) are reportedly T2R4 antagonists, with IC 50 s of 3.2 µM and 59 nM respectively; Nα,Nα-bis(carboxymethyl)-L-lysine acts rather as an inverse agonist (Pydi, Sobotkiewicz, et al, 2014).…”

Section: Accepted Manuscriptmentioning

confidence: 99%