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1.
Mol Pharmacol ; 99(5): 319-327, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33824185

RESUMO

Children have difficulty swallowing capsules. Yet, when presented with liquid formulations, children often reject oral medications due to their intense bitterness. Presently, effective strategies to identify methods, reagents, and tools to block bitterness remain elusive. For a specific bitter-tasting drug, identification of the responsible bitter receptors and discovery of antagonists for those receptors can provide a method to block perceived bitterness. We have identified a compound (6-methylflavone) that can block responses to an intensely bitter-tasting anti-human immunodeficiency virus (HIV) drug, tenofovir alafenamide (TAF), using a primary human taste bud epithelial cell culture as a screening platform. Specifically, TAS2R39 and TAS2R1 are the main type 2 taste receptors responding to TAF observed via heterologously expressing specific TAS2R receptors into HEK293 cells. In this assay, 6-methylflavone blocked the responses of TAS2R39 to TAF. In human sensory testing, 8 of 16 subjects showed reduction in perceived bitterness of TAF after pretreating (or "prerinsing") with 6-methylflavone and mixing 6-methylflavone with TAF. Bitterness was completely and reliably blocked in two of these subjects. These data demonstrate that a combined approach of human taste cell culture-based screening, receptor-specific assays, and human psychophysical testing can successfully discover molecules for blocking perceived bitterness of pharmaceuticals, such as the HIV therapeutic TAF. Our hope is to use bitter taste blockers to increase medical compliance with these vital medicines. SIGNIFICANCE STATEMENT: Identification of a small molecule that inhibits bitter taste from tenofovir alafenamide may increase the compliance in treating children with human immunodeficiency virus infections.


Assuntos
Adenina/análogos & derivados , Aromatizantes/administração & dosagem , Aromatizantes/química , Papilas Gustativas/efeitos dos fármacos , Paladar/efeitos dos fármacos , Adenina/efeitos adversos , Adenina/química , Adulto , Alanina , Antivirais/efeitos adversos , Antivirais/química , Linhagem Celular , Feminino , Flavonas/administração & dosagem , Flavonas/química , Células HEK293 , Humanos , Masculino , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Papilas Gustativas/metabolismo , Tenofovir/análogos & derivados
2.
Br J Pharmacol ; 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38745397

RESUMO

BACKGROUND AND PURPOSE: Many medications taste intensely bitter. The innate aversion to bitterness affects medical compliance, especially in children. There is a clear need to develop bitter blockers to suppress the bitterness of vital medications. Bitter taste is mediated by TAS2R receptors. Because different pharmaceutical compounds activate distinct sets of TAS2Rs, targeting specific receptors may only suppress bitterness for certain, but not all, bitter-tasting compounds. Alternative strategies are needed to identify universal bitter blockers that will improve the acceptance of every medication. Taste cells in the mouth transmit signals to afferent gustatory nerve fibres through the release of ATP, which activates the gustatory nerve-expressed purine receptors P2X2/P2X3. We hypothesized that blocking gustatory nerve transmission with P2X2/P2X3 inhibitors (e.g. 5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidine-2,4-diamine [AF-353]) would reduce bitterness for all medications and bitter compounds. EXPERIMENTAL APPROACH: Human sensory taste testing and mouse behavioural analyses were performed to determine if oral application of AF-353 blocks perception of bitter taste and other taste qualities but not non-gustatory oral sensations (e.g. tingle). KEY RESULTS: Rinsing the mouth with AF-353 in humans or oral swabbing it in mice suppressed the bitter taste and avoidance behaviours of all compounds tested. We further showed that AF-353 suppressed other taste qualities (i.e. salt, sweet, sour and savoury) but had no effects on other oral or nasal sensations (e.g, astringency and oral tingle). CONCLUSION AND IMPLICATIONS: This is the first time a universal, reversible taste blocker in humans has been reported. Topical application of P2X2/P2X3 inhibitor to suppress bitterness may improve medical compliance.

3.
PLoS One ; 16(10): e0256989, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34614010

RESUMO

The taste stimulus glucose comprises approximately half of the commercial sugar sweeteners used today, whether in the form of the di-saccharide sucrose (glucose-fructose) or half of high-fructose corn syrup (HFCS). Therefore, oral glucose has been presumed to contribute to the sweet taste of foods when combined with fructose. In light of recent rodent data on the role of oral metabolic glucose signaling, we examined psychopharmacologically whether oral glucose detection may also involve an additional pathway in humans to the traditional sweet taste transduction via the class 1 taste receptors T1R2/T1R3. In a series of experiments, we first compared oral glucose detection thresholds to sucralose thresholds without and with addition of the T1R receptor inhibitor Na-lactisole. Next, we compared oral detection thresholds of glucose to sucralose and to the non-metabolizable glucose analog, α-methyl-D-glucopyranoside (MDG) without and with the addition of the glucose co-transport component sodium (NaCl). Finally, we compared oral detection thresholds for glucose, MDG, fructose, and sucralose without and with the sodium-glucose co-transporter (SGLT) inhibitor phlorizin. In each experiment, psychopharmacological data were consistent with glucose engaging an additional signaling pathway to the sweet taste receptor T1R2/T1R3 pathway. Na-lactisole addition impaired detection of the non-caloric sweetener sucralose much more than it did glucose, consistent with glucose using an additional signaling pathway. The addition of NaCl had a beneficial impact on the detection of glucose and its analog MDG and impaired sucralose detection, consistent with glucose utilizing a sodium-glucose co-transporter. The addition of the SGLT inhibitor phlorizin impaired detection of glucose and MDG more than it did sucralose, and had no effect on fructose, further evidence consistent with glucose utilizing a sodium-glucose co-transporter. Together, these results support the idea that oral detection of glucose engages two signaling pathways: one that is comprised of the T1R2/T1R3 sweet taste receptor and the other that utilizes an SGLT glucose transporter.


Assuntos
Glucose/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Proteínas de Transporte de Sódio-Glucose/metabolismo , Paladar , Adulto , Feminino , Glucose/análise , Humanos , Masculino , Pessoa de Meia-Idade , Transdução de Sinais
4.
Am J Clin Nutr ; 103(1): 50-60, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26607941

RESUMO

BACKGROUND: Individuals who adhere to reduced-sodium diets come to prefer less salt over time, but it is unclear whether sweet taste perception is modulated by reduced sugar intake. OBJECTIVE: The objective was to determine how a substantial reduction in dietary intake of simple sugars affects sweetness intensity and pleasantness of sweet foods and beverages. DESIGN: Healthy men and women aged 21-54 y participated for 5 mo. After the baseline month, 2 subject groups were matched for demographic characteristics, body mass index, and intake of simple sugars. One group (n = 16; 13 of whom completed key experimental manipulations) was randomly assigned to receive a low-sugar diet during the subsequent 3 mo, with instructions to replace 40% of calories from simple sugars with fats, proteins, and complex carbohydrates. The other (control) group (n = 17; 16 of whom completed the study) did not change their sugar intake. During the final month, both groups chose any diet they wished. Each month subjects rated the sweetness intensity and pleasantness of vanilla puddings and raspberry beverages that varied in sucrose concentration. RESULTS: ANOVA showed no systematic differences between groups in rated sweetness during the baseline or first diet month. During the second diet month, the low-sugar group rated low-sucrose pudding samples as more intense than did the control group (significant group-by-concentration interaction, P = 0.002). During the third diet month, the low-sugar subjects rated both low and high concentrations in puddings as ∼40% sweeter than did the control group (significant effect of group, P = 0.01). A weaker effect on rated sweetness was obtained for the beverages. Rated pleasantness was not affected for either of the stimuli. CONCLUSIONS: This experiment provides empirical evidence that changes in consumption of simple sugars influence perceived sweet taste intensity. More work is needed to determine whether sugar intake ultimately shifts preferences for sweet foods and beverages. This trial was registered at clinicaltrials.gov as NCT02090478.


Assuntos
Dieta/psicologia , Sacarose Alimentar/administração & dosagem , Comportamento Alimentar/psicologia , Preferências Alimentares/psicologia , Edulcorantes/administração & dosagem , Paladar , Adulto , Análise de Variância , Ingestão de Energia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Percepção , Prazer
5.
Mol Metab ; 2(3): 270-80, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24049739

RESUMO

Messages describing foods constitute a pervasive form of reward cueing. Different descriptions may produce particular appeal depending upon the individual. To examine the extent to which verbal descriptors and individual differences interact to influence food preferences, we used functional magnetic resonance imaging to measure brain responses to the same low-calorie drinks preceded by the spoken verbal descriptor "treat" or "healthy" in 27 subjects varying in BMI, eating style and reward sensitivity. Subjects also sampled a prototypical milkshake treat. Despite the fact that the verbal descriptor had no influence on pleasantness ratings, preferential responses to the low-calorie drinks labeled "treat" vs. "healthy" were observed in the midbrain and hypothalamus. These same regions were also preferentially responsive to the prototypical treat. These results reveal a previously undocumented influence of verbal descriptors on brain circuits regulating energy homeostasis.

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