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Summary: Neurodegeneration in central nervous system disorders is linked to dysregulated neuronal calcium. Direct inhibition of glutamate-induced neuronal calcium influx, particularly via N-methyl-D-aspartate receptors (NMDAR), has led to adverse effects and clinical trial failures. A more feasible approach is to modulate NMDAR activity or calcium signaling indirectly. In this respect, the calcium-activated non-selective cation channel transient receptor potential melastatin 4 (TRPM4) has been identified as a promising target. However, high affinity and specific antagonists are lacking. Here, we conducted high-throughput screening of a compound library to identify high affinity TRPM4 antagonists. This yielded five lead compound series with nanomolar half-maximal inhibitory concentration values. Through medicinal chemistry optimization of two series, we established detailed structure-activity relationships and inhibition of excitotoxicity in neurons. Moreover, we identified their potential binding site supported by electrophysiological measurements. These potent TRPM4 antagonists are promising drugs for treating neurodegenerative disorders and TRPM4-related pathologies, potentially overcoming previous therapeutic challenges.

Freshwater salinization is a growing global concern impacting human and ecosystem needs with impacts to water availability for human and ecological uses. In the Upper Colorado River Basin (UCRB), dissolved solids in streams compound ongoing water supply challenges to further limit water availability and cause economic damages. Much effort has been dedicated to understanding dissolved solid sources, transport, and management in the region, yet temporal variability in loading from key sources such as irrigated lands and the influence of climate on dissolved solids loading remains unknown. Quantifying the contributions and temporal variability of dissolved solids loads from irrigated lands may benefit salinity management efforts. This study applies a time-varying (dynamic) modeling approach to predict annual dissolved solids loads across the UCRB from 1986 through 2017. Between 66% and 82% of the total accumulated dissolved solids load in the basin is from groundwater (storage and baseflow). Our findings link climate, irrigation, and groundwater, and confirm large storage contributions that have declined slightly with time. Dissolved solids loads increase during wet periods and decrease during dry periods, although the relative contributions of different sources vary little with time. Irrigation enhances loading efficiency relative to unirrigated areas through runoff and groundwater, and can locally be a major source of dissolved solids where irrigation occurs. Results indicate that loads from irrigated areas increase when irrigated area and/or water available for runoff increase. Increased regional aridification over the study period may have contributed to decreasing stream salinity through both quicker surface runoff and lagged groundwater storage processes. Study results may be relevant to salinity management in arid environments where water availability is limited and where irrigation influences salinity loading to streams.

In recent years, the thienopyrazole moiety has emerged as a pharmacologically active scaffold with antitumoral and kinase inhibitory activity. In this study, high-throughput screening of 2000 small molecules obtained from the ChemBridge DIVERset library revealed a unique thieno[2,3-c]pyrazole derivative (Tpz-1) with potent and selective cytotoxic effects on cancer cells. Compound Tpz-1 consistently induced cell death at low micromolar concentrations (0.19 μM to 2.99 μM) against a panel of 17 human cancer cell lines after 24 h, 48 h, or 72 h of exposure. Furthermore, an in vitro investigation of Tpz-1’s mechanism of action revealed that Tpz-1 interfered with cell cycle progression, reduced phosphorylation of p38, CREB, Akt, and STAT3 kinases, induced hyperphosphorylation of Fgr, Hck, and ERK 1/2 kinases, and disrupted microtubules and mitotic spindle formation. These findings support the continued exploration of Tpz-1 and other thieno[2,3-c]pyrazole-based compounds as potential small-molecule anticancer agents.