Differential interactions of nateglinide and repaglinide on the human β-cell sulphonylurea receptor 1

Repaglinide and nateglinide represent a new class of insulin secretagogues, structurally unrelated to sulphonylureas, that were developed for the treatment of type 2 diabetes. The inhibitory effect of these drugs was investigated on recombinant wild-type and mutant Kir6.2/SUR1 channels expressed in HEK293 cells. Nateglinide and repaglinide dose-dependently inhibited whole-cell Kir6.2/SUR1 currents with half-maximal inhibitory concentration (IC50) values of 800 and 21 nmol/l, respectively. Mutation of serine 1237 in SUR1 to tyrosine (S1237Y) abolished tolbutamide and nateglinide block, suggesting that these drugs share a common point of interaction on the SUR1 subunit of the ATP-sensitive K+ channel. In contrast, repaglinide inhibition was unaffected by the S1237Y mutation (IC50 = 23 nmol/l). Radioligand binding studies revealed a single high-affinity binding site for [H-3]repaglinide on membranes prepared from HEK293 cells expressing wildtype (equilibrium dissociation constant [K-D] = 0.40 nmol/l) or mutant (K-D, = 0.31 nmol/l) Kir6.2/SUR1 channels. Nateglinide and tolbutamide displaced [(3) H]repaglinide binding to wild-type channels with IC50 values of 0.7 and 26 mumol/l, respectively, but produced <10% displacement of [H-3]repaglinide bound to mutant channels. This is consistent with the idea that binding of nateglinide and tolbutamide, but not repaglinide, is abolished by the SUR1[S1237Y] mutation and that the binding site for repaglinide is not identical to that of nateglinde/tolbutamide. These results are discussed in terms of a conformational analysis of the drug molecules.