Synthesis of Modified 4H‐1,2,4‐Benzothiadiazine‐1,1‐dioxides and Determination of their Affinity and Selectivity for Different Types of KATP Channels

4H‐1,2,4‐Benzothiadiazine‐1,1‐dioxides with various substituents in positions 3, 5, and 7 were synthesized and tested as K_ATP channel agonists in artificial cell systems (CHO cells transfected with SUR1/Kir6.2, and HEK 293 transfected with SUR2B/Kir6.1) as model systems for insulin‐secreting pancreatic β‐cells and for smooth muscle cells, respectively. The effects of agonists were tested in intact cells using DiBAC4(3) bis‐(1,3‐dibarbituric acid)trimethine oxanol] as a membrane potential dye, and the results compared with their binding affinity for the SUR2B‐type K_ATP channels using the radioligand ³H]P1075. Compounds with cycloalkyl and (cycloalkyl)methyl side chains in position 3 had higher affinities towards the SUR2B/Kir6.1 receptor compared with the parent compound diazoxide ( 1 a ). Compounds with bulky, nonpolar residues in position 3 exhibited remarkable selectivity for SUR2B‐type K_ATP channels. The compound substituted with a bulky (1‐adamantyl)methyl residue exhibited micromolar affinity and activity on SUR2B‐type K_ATP channels without being able to activate the SUR1‐type K_ATP channels.