biostudies-literatureDelpire EHHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)HHS | NIH | National Institute of Diabetes and Digestive and Kidney DiseasesNIDDK NIH HHSFondation LeducqC324-C340https://www.ebi.ac.uk/biostudies/studies/S-EPMC8294628biostudies-literatureUnknown320(3)For about half a century, the pharmacology of electroneutral cation-chloride cotransporters has been dominated by a few drugs that are widely used in clinical medicine. Because these diuretic drugs are so good at what they do, there has been little incentive in expanding their pharmacology. The increasing realization that cation-chloride cotransporters are involved in many other key physiological processes and the knowledge that different tissues express homologous proteins with matching transport functions have rekindled interest in drug discovery. This review summarizes the methods available to assess the function of these transporters and describe the multiple efforts that have made to identify new compounds. We describe multiple screens targeting KCC2 function and one screen designed tAmerican journal of physiology. Cell physiologyAdvances in the development of novel compounds targeting cation-chloride cotransporter physiology.PMC829462817CVD05DK093501R01 DK110375R01 DK093501Delpire EfalseAdvances in the development of novel compounds targeting cation-chloride cotransporter physiology.For about half a century, the pharmacology of electroneutral cation-chloride cotransporters has been dominated by a few drugs that are widely used in clinical medicine. Because these diuretic drugs are so good at what they do, there has been little incentive in expanding their pharmacology. The increasing realization that cation-chloride cotransporters are involved in many other key physiological processes and the knowledge that different tissues express homologous proteins with matching transport functions have rekindled interest in drug discovery. This review summarizes the methods available to assess the function of these transporters and describe the multiple efforts that have made to identify new compounds. We describe multiple screens targeting KCC2 function and one screen designed t2021-01-01T00:00:00Z2021 Mar2025-05-18T12:35:24.966Z2025-04-05T14:05:40.488ZS-EPMC82946283335694810.1152/ajpcell.00566.2020