Sulfonylurea binding sites

Figure 1. Pharmacophore model for the sulfonylurea binding site (amended from Ref. 1).

The absorption of sulfonylureas from the upper gastrointestinal tract is faidy rapid and complete. The agents are transported in the blood as protein-bound complexes. As they are released from protein-binding sites, the free (unbound) form becomes available for diffusion into tissues and to sites of action. Specific receptors are present on pancreatic islet P-ceU surfaces which bind sulfonylureas with high affinity. Binding of sulfonylureas to these receptors appears to be coupled to an ATP-sensitive channel to stimulate insulin secretion. These agents may also potentiate insulin-stimulated glucose transport in adipose tissue and skeletal muscle. 

Methotrexate clearance can be decreased by the coadministration of NSAIDs however, this not usually a problem with the low doses of methotrexate used to treat arthritis. Methotrexate can be displaced from plasma protein binding sites by phenylbutazone, pheny-toin, sulfonylureas, and sulfonamides and certain other antibiotics. The antifolate effects of methotrexate are additive with those of other folate-inhibitory drugs, such as trimethoprim. 

Sulfasalazine can inhibit the absorption of cardiac glycosides and folic acid. It may displace certain drugs, including warfarin, phenytoin, methotrexate, tolbutamide, chlorpropamide, and oral sulfonylureas, from their protein binding sites. Sulfasalazine can diminish the effectiveness of penicillins and estrogen-containing oral contraceptives. 

Some are inhibited by ATP 173 l7 lb and others by eicosanoids475 or inositol hexaphosphate.476 Some of the ATP-sensitive channels contain an ABC transporter subunit and are binding sites for sulfonylureas and other drugs. See discussion on p. 421. A number of human disorders in Kir channels have been identified.468 Tire human Kir channels participate in regulation of resting membrane potentials in K+ homeostasis, control of heart rate, and hormone secretion.468 A third group of K+ channels are dimeric, but each subunit contains two tandem P regions and 4-8 transmembrane helices.455... 

The meglitinides bind with high affinity to a site, distinct from the sulfonylurea receptor site, on the ATP-sensitive potassium channels in pancreatic beta cells and stimulate insulin secretion. After binding, the ATP-dependent potassium channels are closed, reducing potassium efflux and depolarizing the cell membrane. The meglitinides do not have to be internalized in the membrane, in contrast to the sulfonylureas. This may explain their rapid onset of... 

Sulfonylurea from protein binding sites medications... 

The structure of mKATp is not known but it is assumed that it incorporates elements of the two known inward rectifier ATP-sensitive K+ channel proteins, Kv6.1 or Kv6.2. All known sarcolemmal KATp channels contain 4 pore-forming channel proteins and 4 sulfonylurea-binding receptor (SUR) proteins. The SUR has the ATP binding site and, as the name implies, binds sulfonylurea compounds like glibenclamide. Sulfonylurea... 

Drug interactions with sulfonylureas and biguanides are common non-steroidal antiinflammatory drugs, warfarin, alcohol, monoamine oxidase inhibitors, some uricosurics, some antibacterials and some antifungals can interact with them. All increase the risk of hypoglycaemia. The mechanism is probably competition for metabolizing enzymes or displacement from plasma protein binding sites. 

Concomitant use with oral hypoglycemics (sulfonylureas) enhances hypoglycemic effects, probably by displacing sulfonylureas from protein-binding sites. 

Phenylbutazone increases the potency of sulfonylureas as it displaces these drugs from plasma protein-binding sites. Thus, lower dosage is required. 

Application of Global Sequence Similarity to Find an Inhibitor of Acetolactate Synthase. Acetolactate synthase (ALS) Is the site of action of sulfonylurea, Imldazollnone, and trlazolo pyrimidine herbicides (10-14). Their mode of Inhibition and binding sites on ALS were ambiguous, because (1) these herbicides bear no obvious similarity In their chemical structures to those of ALS substrates (pyruvate and acetolactate), cofactors (thiamine pyrophosphate, FAD, and Mg ) and effectors (valine, Isoleuclne, and leucine) and (2) they Inhibit ALS In a mode too complex to be analyzed. 

Little information has been published about the l,2,4-triazolo[l,5-a]-pyrimidines. Their adverse effects on soybean cell growth are reversed by added valine, leucine, and isoleucine inhibition of plant ALS is associated with noncovalent binding of the inhibitor.Similarly, preliminary evidence shows that pyrimidinyl oxobenzoates are potent inhibitors of ALS. " Tobacco and soybean cell lines insensitive to triazolopyrimidines are also insensitive to sulfonylureas and imidazolinones, suggesting that all three classes of inhibitors have overlapping binding sites on ALS. Herbi-cidal selectivity for triazolopyrimidines in crop varieties results from differential uptake and metabolism. ... 

ALS shows a high degree of primary sequence homology with pyruvate carboxylase and pyruvate oxidase the ubiquinone cofactors of pyruvate oxidase inhibit ALS, and it has been proposed that the ubiquinone-binding site of the ancestral enzyme also is the site of both SMM and imidazolinone binding. Recent evidence suggests, however, that these two types of herbicide interact differently with ALS (a) imidazolinones cause a rapid decrease in the levels of extractable ALS activity in maize, whereas SMM does not and can protect the ALS activity from this in vivo effect of imidazolinones and (b) not all imidazolinone-tolerant cell lines are insensitive to sulfonylureas. Sulfonylureas and imidazolinones do not, however, show synergistic inhibition of maize ALS in vitro. ... 

Die cytosolic loop between TMs 13 and 14 (KCO I) and TMs 16-17 (KCO II) were identified as critical for KatpCO binding to SURs (Fig. 4d). T1286 and Ml 290 appeared to be particularly important. Close local association of sulfonylurea and KCO binding regions might represent the structural basis for negative allosteric coupling of the sites. 

Glinides induce insulin secretion similarly (closure of the K. jp channels), but they bind to (he sulfonylurea receptor at a different site and with different... 

Meglitinides are another class of drugs used in the management of Type 2 diabetes. Similar to the sulfonylureas, they bind to the pancreatic p-cells, albeit at a different site, and open the calcium channels. This induces insulin secretion. Repaghnide (Prandin , Novo Nordisk) is an example of the class. 

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