Hu S, Wang S, Fanelli B, Bell P A, Dunning B E, Geisse S, Schmitz R, Boettcher B R
Metabolic and Cardiovascular Disease Department, Novartis Institute for Biomedical Research, Summit, New Jersey 07901, USA.
J Pharmacol Exp Ther. 2000 May;293(2):444-52.
Nateglinide (A-4166) is an amino acid derivative with insulinotrophic action in clinical development for treatment of type 2 diabetes. The aim of this study was to determine whether nateglinide's interaction at the K(ATP) channel/sulfonylurea receptor underlies its more rapid onset and shorter duration of action in animal models. Binding studies were carried out with membranes prepared from RIN-m5F cells and HEK-293 cells expressing recombinant human sulfonylurea receptor 1 (SUR1). The relative order for displacement of [(3)H]glibenclamide in competitive binding experiments with RIN-m5F cell membranes was glibenclamide > glimepiride > repaglinide > glipizide > nateglinide > L-nateglinide > tolbutamide. The results with HEK-293/recombinant human SUR1 cells were similar with the exception that glipizide was more potent than repaglinide. Neither nateglinide nor repaglinide had any effect on the dissociation kinetics for [(3)H]glibenclamide, consistent with both compounds competitively binding to the glibenclamide-binding site on SUR1. Finally, the inability to measure [(3)H]nateglinide binding suggests that nateglinide dissociates rapidly from SUR1. Direct interaction of nateglinide with K(ATP) channels in rat pancreatic beta-cells was investigated with the patch-clamp method. The relative potency for inhibition of the K(ATP) channel was repaglinide > glibenclamide > nateglinide. Kinetics of the inhibitory effect on K(ATP) current showed that the onset of inhibition by nateglinide was comparable to glibenclamide but more rapid than that of repaglinide. The time for reversal of channel inhibition by nateglinide was also faster than with glibenclamide and repaglinide. These results suggest that the unique characteristics of nateglinide are largely the result of its interaction at the K(ATP) channel.
那格列奈（A - 4166）是一种具有促胰岛素分泌作用的氨基酸衍生物，正处于用于治疗2型糖尿病的临床开发阶段。本研究的目的是确定那格列奈在动物模型中起效更快、作用持续时间更短是否归因于其与K(ATP)通道/磺脲类受体的相互作用。使用从RIN - m5F细胞和表达重组人磺脲类受体1（SUR1）的HEK - 293细胞制备的膜进行结合研究。在与RIN - m5F细胞膜的竞争性结合实验中，[(3)H]格列本脲置换的相对顺序为格列本脲＞格列美脲＞瑞格列奈＞格列吡嗪＞那格列奈＞L - 那格列奈＞甲苯磺丁脲。HEK - 293/重组人SUR1细胞的结果相似，不同之处在于格列吡嗪比瑞格列奈更有效。那格列奈和瑞格列奈对[(3)H]格列本脲的解离动力学均无影响，这与两种化合物竞争性结合SUR1上的格列本脲结合位点一致。最后，无法检测到[(3)H]那格列奈结合表明那格列奈从SUR1上快速解离。采用膜片钳方法研究了那格列奈与大鼠胰腺β细胞中K(ATP)通道的直接相互作用。抑制K(ATP)通道的相对效力为瑞格列奈＞格列本脲＞那格列奈。对K(ATP)电流抑制作用的动力学表明，那格列奈抑制的起效与格列本脲相当，但比瑞格列奈更快。那格列奈使通道抑制作用逆转的时间也比格列本脲和瑞格列奈更快。这些结果表明，那格列奈的独特特性很大程度上是其与K(ATP)通道相互作用的结果。
