[en] The present review will focus on loop diuretics and more specifically on the mode of action of sulfonylurea diuretics such as torasemide (TOR). TOR has two major sites of action in the thick ascending limb of the loop of Henle (TAL). It interacts with the Na+2Cl-K+ -cotransporter localized in the luminal membrane of the TAL segment, and it blocks Cl- -channels in the basolateral cell membrane of these TAL-cells. The former effect, with an IC50 of 3.10^-7 mol/l, requires very low and the latter 100 times larger concentrations. In the current study derivatives of TOR were designed in which the totyl (R1) and the isopropyl (R2) moieties of TOR were replaced by cyclo-alkyl residues. From previous studies we knew that apolar subsituents at these two sites of the sulfonylurea diuretic preserved the diuretic potency to some extent, but increased strongly the lipophilicity of the molecule. Both R1 and R2 were varied between cyclo-hexyl and cyclo-octyl. For each compound the pka, reflecting mostly the acidity of the sulfonylurea group, the octanol/water partition, and the inhibitory potency (IC50) in isolated in vitro perfused rabbit cortical TAL segments (cTAL) were determined. The addition of the compound to the bath reflects its inhibitory potency on Cl- -channels, and the addition to the lumen perfusate reflects the inhibitory potency on the Na+2Cl-K+ -cotransporter. The present data indicate that compounds with cyclo-hexyl as R2, of the cyclo-octyl and cyclo-hexyl residues at R1 had an inhibitory potency on the Na+2Cl-K+ -cotransporter comparable to TOR. These compounds are highly lipophilic, and their pka-values are between 7.7 and 9.0. The present data indicate that, on the basis of the TOR-structure, lipophilic specif inhibitors with very high affinity to the Na+2Cl-K+ -cotransporter can be designed.
