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Vol. 293, Issue 2, 444-452, May 2000
-Cell KATP Channel
Activity and Membrane-Binding Studies with Nateglinide: A Comparison
with Sulfonylureas and Repaglinide
Metabolic and Cardiovascular Disease Department, Novartis Institute
for Biomedical Research, Summit, New Jersey (S.H., S.W., B.F., P.A.B.,
B.E.D., B.R.B.); and Core Technology Area, Novartis Pharma Research,
Basel, Switzerland (S.G., R.S.)
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 > 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
[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 KATP
channels in rat pancreatic 
-cells was investigated with the
patch-clamp method. The relative potency for inhibition of the
KATP channel was repaglinide > glibenclamide > nateglinide. Kinetics of the inhibitory effect on
KATP 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
KATP channel.
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