Nateglinide, a d-Phenylalanine Derivative Lacking Either a Sulfonylurea or Benzamido Moiety, Specifically Inhibits Pancreatic β-Cell-Type K_ATP Channels

Abstract

A novel antidiabetic agent, nateglinide, is a D-phenylalanine derivative lacking either a sulfonylurea or benzamido moiety. We examined with the patch-clamp method the effect of nateglinide on recombinant ATP-sensitive K ϩ (K ATP ) channels expressed in human embryonic kidney 293T cells transfected with a Kir6.2 subunit and either of a sulfonylurea receptor (SUR) 1, SUR2A, and SUR2B. In inside-out patches, nateglinide reversibly inhibited the spontaneous openings of all three types of SUR/Kir6.2 channels. Nateglinide inhibited SUR1/Kir6.2 channels with high and low affinities (K i ϭ 75 nM and 114 M) but SUR2A/Kir6.2 and SUR2B/Kir6.2 channels only with low affinity (K i ϭ 105 and 111 M, respectively). Nateglinide inhibited the K ATP current mediated by Kir6.2 lacking C-terminal 26 amino acids only with low affinity (K i ϭ 290 M) in the absence of SUR. Replacement of serine at position 1237 of SUR1 to tyrosine [SUR1(S1237Y)] specifically abolished the high-affinity inhibition of SUR1/Kir6.2 channels by nateglinide. MgADP or MgUDP (100 M) augmented the inhibitory effect of nateglinide on SUR1/Kir6.2 but not SUR1(S1237Y)/Kir6.2 or SUR2A/Kir6.2 channels. This augmenting effect of MgADP was also observed with the SUR1/Kir6.2(K185Q) channel, which was not inhibited by MgADP, but not with the SUR1(K1384A)/Kir6.2 channel, which was not activated by MgADP. These results indicate that therapeutic concentrations of nateglinide (ϳ10 M) may selectively inhibit pancreatic type SUR1/Kir6.2 channels through SUR1, especially when the channel is activated by intracellular MgADP, even though the agent does not contain either a sulfonylurea or benzamido moiety. ATP-sensitive Kϩ (K ATP ) channels are inhibited by intracellular ATP and activated by ADP and thus provide a link between the cellular metabolic state and excitability (Ashcroft, 1988;Terzic et al., 1995). These channels are associated with such cellular functions as insulin secretion, cardiac preconditioning, vasodilatation, and neuroprotection (Ashcroft, 1988;Terzic et al., 1995;Nichols et al., 1996;Quayle et al., 1997;Yamada et al., 2001;Miki et al., 2002). K ATP channels are composed of an ATP-binding cassette protein, sulfonylurea receptor (SUR), and an inwardly rectifying K ϩ channel (Kir) subunit, Kir6.0 (Aguilar-Bryan et al., 1995;Inagaki et al., 1995Inagaki et al., , 1996Inagaki et al., , 1997Sakura et al., 1995;Clement et al., 1997;Shyng and Nichols, 1997). Detailed functional analyses of K ATP channels composed of Kir6.0 and either of three types of SUR (SUR1, SUR2A, and SUR2B) indicate that SUR1, SUR2A, and SUR2B represent pancreatic, cardiac, and vascular smooth muscle types of SUR, respectively (AguilarBryan et al

The Impact of ATP-Sensitive K+ Channel Subtype Selectivity of Insulin Secretagogues for the Coronary Vasculature and the Myocardium

“…2). Most interestingly, the glinides fall into two classes-either type B ligands, like the benzoic acid derivatives meglitinide (13) and repaglinide (15,16), or type A ligands, like nateglinide (15,17) and mitiglinide (18). Molecular modeling has shown that nateglinide resembles tolbutamide, whereas repaglinide resembles the carboxamido part of glibenclamide; however, the piperidine ring of repaglinide protrudes out of the common pharmacophore (15).…”

“…in 2); some data from isolated organs are also available (19). Among the glinides, nateglinide (17) and mitiglinide (18) were shown to be ϳ1,000ϫ selective for the Kir6.2/SUR1 over the Kir6.2/ SUR2 channels. This exquisite selectivity is in line with the classification of these secretagogues as type A ligands and is in sharp contrast to the benzoic acid derivatives, meglitinide and repaglinide, which are type B ligands and do not discriminate much between the channel subtypes (2,16).…”

Imaging Docking and Fusion of Insulin Granules Induced by Antidiabetes Agents

“…It has been concretely shown that sulfonylureas bind the SUR subunit and that the SUR moiety on sulfonylureas, which functions as a ligand for SUR receptors, is required for causing insulin release (11,19). Glinides such as mitiglinide lack the SUR moiety present on sulfonylureas, which facilitate these ligands binding to their cognate receptors (20,21). Nevertheless, mitiglinide was shown to inhibit [ 3 H]glibenclamide binding to SUR1 and caused increased [Ca 2ϩ ] i (22).…”

Allicin, a SUR2 opener: possible mechanism for the treatment of diabetic hypertension in rats

“…It is known that glibenclamide causes hypertension due to blocking of SUR2 (blood vessel) (Seino, 2003). Nateglinide has high affinity to pancreatic SUR1/Kir6.2 channels and very less affinity for blood vessel receptors SUR2A/Kir6.2, so blockade of SUR1/ Kir6.2 channels by nateglinide produces antidiabetic effect but not hypertension as a side effect due to free SUR2A/Kir6.2 receptors (Chachin et al, 2003). It means that when combination of nateglinide and allicin is given, allicin is free to bind on SUR2 receptor as opener causing vasodilation while glibenclamide blocks both SUR1 as well as SUR2, causing vasoconstriction.…”

“…K ATP channels can be nonselectively blocked in pancreatic as well as nonpancreatic tissues by some sulfonylurea like glibenclamide; it causes hypertension as a side effect due to blocking of SUR2 while nateglinide specifi cally blocked SUR1/Kir6.2 channels with high affi nities but SUR2A/Kir6.2 and SUR2B/Kir6.2 channels only with low affi nity. So nateglinide do not produced hypertension as a side effect (Chachin et al, 2003). K ATP channel openers targeting the pancreatic β-cell are used therapeutically to reduce insulin secretion.…”