Interaction of the sulfonylthiourea HMR 1833 with sulfonylurea receptors and recombinant ATP-sensitive K(+) channels: comparison with glibenclamide.
The novel sulfonylthiourea 1-[[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl]-3-methylthiourea (HMR 1883), a blocker of ATP-sensitive K(+) channels (K(ATP) channels), has potential against ischemia-induced arrhythmias. Here, the interaction of HMR 1883 with sulfonylurea receptor (SUR) subtypes and recombinant K(ATP) channels is compared with that of the standard sulfonylurea, glibenclamide, in radioligand receptor binding and electrophysiological experiments. HMR 1883 and glibenclamide inhibited [(3)H]glibenclamide binding to SUR1 with K(i) values of 63 microM and 1.5 nM, and [(3)H]opener binding to SUR2A/2B with K(i) values of 14/44 microM and 0.5/2.8 microM, respectively (values at 1 mM MgATP). The interaction of HMR 1883 with the SUR2 subtypes was more sensitive to inhibition by MgATP and MgADP than that of glibenclamide. In inside-out patches and in the absence of nucleotides, HMR 1883 inhibited the recombinant K(ATP) channels from heart (Kir6.2/SUR2A) and nonvascular smooth muscle (Kir6.2/SUR2B) with IC(50) values of 0.38 and 1.2 microM, respectively; glibenclamide did not discriminate between these channels (IC(50) approximately 0.026 microM). In whole cells, the recombinant vascular K(ATP) channel, Kir6.1/SUR2B, was inhibited by HMR 1883 and glibenclamide with IC(50) values of 5.3 and 0.043 microM, respectively. The data show that the sulfonylthiourea exhibits a selectivity profile quite different from that of glibenclamide with a major loss of affinity toward SUR1 and slight preference for SUR2A. The stronger inhibition by nucleotides of HMR 1883 binding to SUR2 (as compared with glibenclamide) makes the sulfonylthiourea an interesting tool for further investigation.
Russ
U
U
Department of Pharmacology, Medical Faculty, University of Tübingen, Germany.
Lange
U
U
Löffler-Walz
C
C
Hambrock
A
A
Quast
U
U
D018528:ATP-Binding Cassette Transporters; D001665:Binding Sites; D002478:Cells, Cultured; D005905:Glyburide / Q000494:pharmacology*; D006801:Humans; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D011869:Radioligand Assay; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D064233:Sulfonylurea Receptors; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology*
C577507:ABCC8 protein, human; C577510:ABCC9 protein, human; D018528:ATP-Binding Cassette Transporters; D008565:Membrane Proteins; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D011994:Recombinant Proteins; D013449:Sulfonamides; D064233:Sulfonylurea Receptors; C117780:mitochondrial K(ATP) channel; C114623:clamikalant; D013890:Thiourea; D005905:Glyburide