Identification of positive modulators of TRPM5 channel from a high-throughput screen using a fluorescent membrane potential assay
| Autor: | Raveglia Luca Francesco, Richard M. Myers, Caterina Virginio, Mark Sabat, Daniela Brodbeck, Laurent Brault, Selena Nola, Alessio Barilli, Laura Aldegheri |
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| Rok vydání: | 2022 |
| Předmět: |
Membrane potential
Chemistry TRPM Cation Channels Biochemistry Small molecule Electrophysiological Phenomena High-Throughput Screening Assays Membrane Potentials Analytical Chemistry Transient receptor potential channel Electrophysiology Transient Receptor Potential Channels Molecular Medicine TRPM5 Selectivity Ion channel Intracellular Fluorescent Dyes Biotechnology |
| Zdroj: | SLAS Discovery. 27:55-64 |
| ISSN: | 2472-5552 |
| DOI: | 10.1016/j.slasd.2021.10.004 |
| Popis: | Transient Receptor Potential Melastatin 5 (TRPM5) is an intracellular calcium-activated cation-selective ion channel expressed in a variety of cell types. Dysfunction of this channel has recently been implied in a range of disease states including diabetes, enteric infections, inflammatory responses, parasitic infection and other pathologies. However, to date, agonists and positive modulators of this channel with sufficient selectivity to enable target validation studies have not been described, limiting the evaluation of TRPM5 biology and its potential as a drug target. We developed a high-throughput assay using a fluorescent membrane potential dye and a medium- and high-throughput electrophysiology assay using QPatch HTX and SyncroPatch 384PE. By employing these assays, we conducted a primary screening campaign and identified hit compounds as TRPM5 channel positive modulators. An initial selectivity profile confirmed hit selectivity to TRPM5 and is presented here. These small molecule TRPM5 compounds have a high potential both as early tool compounds to enable pharmacological studies of TRPM5 and as starting points for the development of potent, selective TRPM5 openers or positive modulators as novel drugs targeting several pathological states. |
| Databáze: | OpenAIRE |
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