Receptor binding sites of hypoglycemic sulfonylureas and related [(acylamino)alkyl]benzoic acids

Brown, George R.; Foubister, Alan J.

doi:10.1021/jm00367a016

Cited by 51 publications

(46 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2). These compounds bound to SUR1 with ϳ1,000ϫ higher affinity than the short-chain sulfonylureas, and it was hypothesized that the binding pocket of glibenclamide comprises two parts (or subsites): site A, which accommodates the old (short-chain sulfonylurea) part of the compound, and site B for the new carboxamido part (12). This "two-sites hypothesis" of glibenclamide binding was supported by the finding that meglitinide, the carboxamido-part of glibenclamide with the negative charge provided by benzoic acid (Fig.…”

Section: The Sur Binding Site(s) For Sulfonylureas and Glinidesmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2004

View full text Add to dashboard Cite

Insulin secretagogues (sulfonylureas and glinides) increase insulin secretion by closing the ATP-sensitive K ؉ channel (K ATP channel) in the pancreatic ␤-cell membrane. K ATP channels subserve important functions also in the heart. First, K ATP channels in coronary myocytes contribute to the control of coronary blood flow at rest and in hypoxia. Second, K ATP channels in the sarcolemma of cardiomyocytes (sarcK ATP channels) are required for adaptation of the heart to stress. In addition, the opening of sarcK ATP channels and of K ATP channels in the inner membrane of mitochondria (mitoK ATP channels) plays a central role in ischemic preconditioning. Opening of sarcK ATP channels also underlies the STsegment elevation of the electrocardiogram, the primary diagnostic tool for initiation of lysis therapy in acute myocardial infarction. Therefore, inhibition of cardiovascular K ATP channels by insulin secretagogues is considered to increase cardiovascular risk. Electrophysiological experiments have shown that the secretagogues differ in their selectivity for the pancreatic over the cardiovascular K ATP channels, being either highly selective (ϳ1,000؋; short sulfonylureas such as nateglinide and mitiglinide), moderately selective (10 -20؋; long sulfonylureas such as glibenclamide [glyburide]), or essentially nonselective (<2؋; repaglinide). New binding studies presented here give broadly similar results. In clinical studies, these differences are not yet taken into account. The hypothesis that the in vitro selectivity of the insulin secretagogues is of importance for the cardiovascular outcome of diabetic patients with coronary artery disease needs to be tested. Diabetes 53 (Suppl. 3):S156 -S164, 2004 I nsulin secretagogues are widely prescribed in the treatment of type 2 diabetes. They close the ATPsensitive K ϩ channel (K ATP channel) in the membrane of the pancreatic ␤-cell, thereby depolarizing the cell and triggering insulin secretion. K ATP channels are gated by intracellular nucleotides with ATP inducing channel closure and MgADP channel opening. The ␤-cell is special in that physiological changes in plasma glucose change the intracellular ATP and ADP concentrations such that the channel opens and closes; hence, the channel functions as the glucose sensor in this cell (1-3). K ATP channel subtypes are found in many cell types. The generation of mice in which the genes for the K ATP channel subunits were deleted have shed new light on the diverse functions of the K ATP channels in various tissues in physiological and pathophysiological conditions (1). In brain, K ATP channels are involved in actions as diverse as the control of glucose homeostasis and the regulation of neuronal excitability in hypoxia (1); however, the insulin secretagogues do not cross the blood-brain barrier easily enough to affect these channels at therapeutic plasma levels (4). In several vascular beds, the K ATP channel in the vascular myocytes is involved in the regulation of vessel tone; opening is triggered in particular by stimuli inc...

show abstract

Section: The Sur Binding Site(s) For Sulfonylureas and Glinidesmentioning

confidence: 99%

“…2). The sulfonylureas and glinides have in common the negative charge and the central phenyl ring, suggesting that the binding sites for a type A ligand such as tolbutamide and for a type B ligand such as meglitinide overlap to accommodate these parts (12).…”

Section: The Sur Binding Site(s) For Sulfonylureas and Glinidesmentioning

confidence: 99%

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

et al. 2004

View full text Add to dashboard Cite

show abstract

“…Thus from the data of the present study it would follow that both putative sites require the presence of Mg2' ions for the functional coupling of inhibitory receptor and KATP. However, in the two-site model for the interaction of sulphonylureas with their recognition site, it was suggested (Brown & Foubister, 1984) Panten et al, 1989 (no Mg2' added) with Schwanstecher et al, 1991 (1 mM Mg2' present)). Following these observations and given the large reduction in the Hill coefficients for tolbutamide and glibenclamide in the absence of Mg2+ to values substantially less than one, we suggest that the absence of intracellular Mg2' functionally uncouples the sulphonylurea receptor from the KATP.…”

Section: Whole-cell Studiesmentioning

confidence: 99%

Mg²⁺‐dependent inhibition of K_ATP by sulphonylureas in CRI‐G1 insulin‐secreting cells

Lee

Ozanne

Hales

et al. 1994

British J Pharmacology

View full text Add to dashboard Cite

“…As it has previously been argued that the highly potent sulphonylureas such as glibenclamide interact with two distinct sites in the plasma membrane of B-cells (one site recognising the sulphonylurea moiety, the other site a different chemical grouping (Brown & Foubister, 1984;Rufer & Losert, 1979), the action of HB699 on the ATP-K' channel was tested using outside-out membrane patches. This drug also produced a marked inhibition of the ATP-K+ channel activity (Figure 4a), with a potency similar to that of glibenclamide (Table 2).…”

Section: Membrane Patch Studiesmentioning

confidence: 99%

Effects of sulphonylureas and diazoxide on insulin secretion and nucleotide‐sensitive channels in an insulin‐secreting cell line

Sturgess

Kozlowski

Carrington

et al. 1988

British J Pharmacology

166

113

View full text Add to dashboard Cite

1 The effects of various sulphonylureas and diazoxide on insulin secretion and the activity of various channels have been studied using tissue culture and patch-clamp methods in an insulinsecreting cell line derived from a rat islet cell tumour. 2 Tolbutamide, glibenclamide and HB699 increased the rate of insulin release by 2-5 fold. The concentrations of tolbutamide and glibenclamide giving half-maximum effects on insulin secretion were approximately 40pM and 0.2pm, respectively. 3 Diazoxide (0.6-1.0mM) per se, had either no effect or produced a small increase in insulin secretion, whereas when secretion was maximally stimulated by the combination of glucose (3 mM) and leucine (20mM), it produced inhibition. Tolbutamide-induced release was also inhibited by diazoxide. 4 Tolbutamide, glibenclamide, HB699 and HB985 reduced the open-state probability of the ATP-K+ channel in a dose-dependent manner. Tolbutamide and glibenclamide were shown to be effective regardless of which side of the membrane they were applied. 5 In whole cell recording, in which the total ATP-sensitive K+ conductance of the cell could be measured, dose-inhibition curves for tolbutamide and glibenclamide were constructed, resulting in Ki values of 17pM and 27nm, respectively. The value of Ki for tolbutamide was unchanged when ATP (0.1 mM) was present in the electrode. 6 Diazoxide (0.6mM) activated the ATP-K+ channels only when they had first been inhibited by intracellular ATP (0.1 mM) or bath applied tolbutamide (3-30 pM). The inhibition produced by glibenclamide could not be reversed by diazoxide. 7 Neither tolbutamide (1.0mM) nor glibenclamide (10 M) altered the open-state probability of the Ca2 + -activated K+ channel or the Ca2 + -activated non-selective cation channel which are present in this cell line. 8 It is concluded that the sulphonylureas and related hypoglycaemic drugs and diazoxide regulate insulin secretion by direct effects on the ATP-K+ channel or a protein closely associated with this channel.

show abstract

Receptor binding sites of hypoglycemic sulfonylureas and related [(acylamino)alkyl]benzoic acids

Cited by 51 publications

References 2 publications

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

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

Mg²⁺‐dependent inhibition of K_ATP by sulphonylureas in CRI‐G1 insulin‐secreting cells

Effects of sulphonylureas and diazoxide on insulin secretion and nucleotide‐sensitive channels in an insulin‐secreting cell line

Contact Info

Product

Resources

About

Receptor binding sites of hypoglycemic sulfonylureas and related [(acylamino)alkyl]benzoic acids

Cited by 51 publications

References 2 publications

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

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

Mg2+‐dependent inhibition of KATP by sulphonylureas in CRI‐G1 insulin‐secreting cells

Effects of sulphonylureas and diazoxide on insulin secretion and nucleotide‐sensitive channels in an insulin‐secreting cell line

Contact Info

Product

Resources

About

Mg²⁺‐dependent inhibition of K_ATP by sulphonylureas in CRI‐G1 insulin‐secreting cells