Inhibition of ATP-sensitive K+-channels by a sulfonylurea analogue with a phosphate group

Hypoglycaemic sulfortylureas initiate insulin secretion by direct inhibition of ATP-sensitive K--channels in the pancreatic beta-cells. These channels are composed of two proteins, a pore-forming subunit (K(IR)6.2 in the case of beta-cells) and a regulatory subunit, the sulfonylurea receptor (SUR). In the present study we characterised the interaction with SURs of the new sulfonylurea analogues 5-chloro-N-[2-(4-hydroxyphenyl)ethyl]-2-methoxvbenzamide (compound I) and {4-[2-(5-chloro-2-methoxybenzamido)ethyl]phenyl}phosphate (compound I). Compounds I and II differ from the sulfonylurea analogue meglitinide only in so far as the carboxylic group of meglitinide is replaced by a hydroxyl group or a phosphate group. respectively. The binding affinities of compound II for the SUR subtypes SUR1 (identified in beta-cells) and SUR2A (identified in heart and skeletal muscle) were higher by 55 or 21-fold, respectively, than the corresponding affinities for compound I. In inside-out patch-clamp experiments compound II inhibited ATP-sensitive K-channels of the SUR1/K(IR)6.2-type (characteristic of beta-cells) with an IC50 value of 0.16 muM which is 6-fold lower than the corresponding value for meglitinide. These findings strongly support the conclusion that the interaction of sulfortylureas and acidic analogues with SURs is favoured by the anionic group of these drugs and that a phosphate group allows more efficient ligand interaction with SUR1 than a carboxylic group. (C) 2002 Elsevier Science Inc. All rights reserved.