Structure-Activity Relationship Studies in a Series of Xanthine Inhibitors of SLACK Potassium Channels.

Gain-of-function mutations in the KCNT1 gene, which encodes the sodium-activated potassium channel known as SLACK, are associated with the rare but devastating developmental and epileptic encephalopathy known as epilepsy of infancy with migrating focal seizures (EIMFS). The design of small molecule inhibitors of SLACK channels represents a potential therapeutic approach to the treatment of EIMFS, other childhood epilepsies, and developmental disorders. Herein, we describe a hit optimization effort centered on a xanthine SLACK inhibitor (8) discovered via a high-throughput screen. Across three distinct regions of the chemotype, we synthesized 58 new analogs and tested each one in a whole-cell automated patch-clamp assay to develop structure-activity relationships for inhibition of SLACK channels. We further evaluated selected analogs for their selectivity versus a variety of other ion channels and for their activity versus clinically relevant SLACK mutants. Selectivity within the series was quite good, including versus hERG. Analog 80 (VU0948578) was a potent inhibitor of WT, A934T, and G288S SLACK, with IC50 values between 0.59 and 0.71 µM across these variants. VU0948578 represents a useful in vitro tool compound from a chemotype that is distinct from previously reported small molecule inhibitors of SLACK channels.

Assessment of Bitterness in Non-Charged Pharmaceuticals with a Taste Sensor: A Study on Substances with Xanthine Scaffold and Allopurinol.

Taste sensors with an allostery approach have been studied to detect non-charged bitter substances, such as xanthine derivatives, used in foods (e.g., caffeine) or pharmaceuticals (e.g., etofylline). In this study, the authors modified a taste sensor with 3-bromo-2,6-dihydroxybenzoic acid and used it in conjunction with sensory tests to assess the bitterness of non-charged pharmaceuticals with xanthine scaffolds (i.e., acefylline and doxofylline), as well as allopurinol, an analogue of hypoxanthine. The results show that the sensor was able to differentiate between different levels of sample bitterness. For instance, when assessing a 30 mM sample solution, the sensor response to acefylline was 34.24 mV, which corresponded to the highest level of bitterness (τ = 3.50), while the response to allopurinol was lowest at 2.72 mV, corresponding to relatively weaker bitterness (τ = 0.50). Additionally, this study extended the application of the sensor to detect pentoxifylline, an active pharmaceutical ingredient in pediatric medicines. These results underscore the taste sensor's value as an additional tool for early-stage assessment and prediction of bitterness in non-charged pharmaceuticals.

Caffeine in Brazil: intake, socioeconomic and demographic determinants, and major dietary sources

Background: The objectives of the study were to describe caffeine intake by 10 years of age or older Brazilian individuals and to investigate possible associations with demographic and socioeconomic determinants as well as the major dietary sources. Methods: The data used are from the personal food consumption module (n= 34,003) of a country-representative household budget survey. Consumed foods and beverages were identified during the application of food diaries. Caffeine contents in food and beverage sources were obtained primarily in national publications. Multivariate regressions were calculated to assess the correlations between population factors and caffeine intake. Results: The daily intake per person was estimated as 115.7 mg, ranging from 84.7 mg, for 10­13 years of age children and adolescents, to 139.8 mg, for individuals with no education. The percentage of individuals whom diet reveals daily caffeine intake higher than 400 mg is up to 3.0 %, according to age groups. Males and individuals living in the Northeast or South regions or in the states of Minas Gerais, Rio de Janeiro, and Espírito Santo are likely to ingest higher contents of the substance. The major dietary sources are coffee (63.1 %) and coffee with milk (24.9 %), cola soft drinks (3.6 %) and yerba mate (1.9 %).Conclusions: Caffeine intake in Brazil is below the recommended limit reference value for adults, and the percentage of individuals whom diet reveals excessive content of caffeine is low. Thus, excessive caffeine intake may not be a health issue in Brazil and depends on the domicile and gender. The major source in the Brazilian diet is coffee.