Abstract

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_ATPchannels is compared with that of the standard sulfonylurea, glibenclamide, in radioligand receptor binding and electrophysiological experiments. HMR 1883 and glibenclamide inhibited [³H]glibenclamide binding to SUR1 withK_i values of 63 μM and 1.5 nM, and [³H]opener binding to SUR2A/2B withK_i values of 14/44 μM and 0.5/2.8 μM, 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_ATPchannels from heart (Kir6.2/SUR2A) and nonvascular smooth muscle (Kir6.2/SUR2B) with IC₅₀ values of 0.38 and 1.2 μM, respectively; glibenclamide did not discriminate between these channels (IC₅₀ ∼ 0.026 μM). In whole cells, the recombinant vascular K_ATP channel, Kir6.1/SUR2B, was inhibited by HMR 1883 and glibenclamide with IC₅₀ values of 5.3 and 0.043 μM, 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.