RT Journal Article
SR Electronic
T1 Pancreatic β-Cell <em>K</em>
<sub>ATP</sub> Channel Activity and Membrane-Binding Studies with Nateglinide: A Comparison with Sulfonylureas and Repaglinide
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 444
OP 452
VO 293
IS 2
A1 Hu, Shiling
A1 Wang, Shuya
A1 Fanelli, Barbara
A1 Bell, Philip A.
A1 Dunning, Beth E.
A1 Geisse, Sabine
A1 Schmitz, Rita
A1 Boettcher, Brian R.
YR 2000
UL http://jpet.aspetjournals.org/content/293/2/444.abstract
AB 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 KATP 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 [3H]glibenclamide in competitive binding experiments with RIN-m5F cell membranes was glibenclamide &gt; glimepiride &gt; repaglinide &gt; glipizide &gt; nateglinide &gt;l-nateglinide &gt; 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 [3H]glibenclamide, consistent with both compounds competitively binding to the glibenclamide-binding site on SUR1. Finally, the inability to measure [3H]nateglinide binding suggests that nateglinide dissociates rapidly from SUR1. Direct interaction of nateglinide with KATPchannels in rat pancreatic β-cells was investigated with the patch-clamp method. The relative potency for inhibition of theKATP channel was repaglinide &gt; glibenclamide &gt; nateglinide. Kinetics of the inhibitory effect onKATP 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 theKATP channel. The American Society for Pharmacology and Experimental Therapeutics