Inhibition of ATP-sensitive K(+)-channels by a sulfonylurea analogue with a phosphate group.
Hypoglycaemic sulfonylureas 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-methoxybenzamide (compound I) and (4-[2-(5-chloro-2-methoxybenzamido)ethyl]phenyl)phosphate (compound II). 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 IC(50) value of 0.16 microM which is 6-fold lower than the corresponding value for meglitinide. These findings strongly support the conclusion that the interaction of sulfonylureas 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.
Hastedt
Katja
K
Institute of Pharmacology and Toxicology, Technical University of Braunschweig, Mendelssohnstrasse 1, D-38106 Braunschweig, Germany.
Panten
Uwe
U
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D019556:COS Cells; D004594:Electrophysiology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D054086:KATP Channels; D010710:Phosphates / Q000737:chemistry; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism* / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000737:chemistry / Q000494:pharmacology*
D018528:ATP-Binding Cassette Transporters; D001549:Benzamides; D007004:Hypoglycemic Agents; D054086:KATP Channels; D010710:Phosphates; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D013453:Sulfonylurea Compounds; C092520:uK-ATP-1 potassium channel; C030516:meglitinide