ATP-sensitive potassium channels openers

Altenbach RJ, Brune ME, Buckner SA et al (2006) Effects of substitution on 9-(3-bromo-4-fluorophenyl)-5, 9-dihydro-3H, 4H-2, 6-dioxa-4-azacyclopenta[b]naphthalene-l, 8-dione, a dihydropyridine ATP-sensitive potassium channel opener. J Med Chem 49 6869-6887... 

Data for the active compounds are presented in Table 6.13. As seen from the data, the structure-activity studies have led to a refinement of the original pharmacophore model (272). It should also be noted that these structures bear a close structural resemblance to (—)-levcromakalim (69), an antihypertensive ATP-sensitive potassium channel opener ... 

C. S. Carr, D. Yellon, Ischemic preconditioning may abolish the protection afforded by ATP-sensitive potassium channel openers in isolated human atrial muscle, Basic Res Cardiol 92, 252-60 (1997). 

R)- and (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (Fig. 4) are intermediates for the synthesis of a number of potential pharmaceuticals, which include ATP-sensitive potassium channel openers for the treatment of incontinence [11], and inhibitors of pyruvate dehydrogenase kinase for the treatment of diabetes [12]. 

Benzopyran derivatives as cardio-selective ATP-sensitive potassium channel openers 13MRM1744. 

Sulfonylureas bind to a 140-kDa high-affinity sulfonylurea receptor (Figure 41-2) that is associated with a beta-cell inward rectifier ATP-sensitive potassium channel. Binding of a sulfonylurea inhibits the efflux of potassium ions through the channel and results in depolarization. Depolarization opens a voltage-gated calcium channel and results in calcium influx and the release of preformed insulin. 

CPZ (9), triflupromazine (11), and fluphenazine (3) inhibited HIT-T15 pancreatic (3-cell ATP-sensitive potassium channels in a dose-dependent manner [254], Reversible inhibition of these channels was observed when they were activated by ATP depletion or by treatment with the channel opener diazoxide. The IC50 values for CPZ (9), triflupromazine (11), and fluphenazine (3) were 1, 4, and 6 xM, respectively. 

The sulfonylureas and the glinides bind to the sulfonylurea receptor on the cell membrane of the beta cells of the pancreatic islets, which causes the ATP-sensitive potassium channel to close. The closed potassium channel increases membrane potential causing the voltage-sensitive calcium channel to open. The sudden influx of calcium begins a cascade of... 

Figure 1. The current through an individual ATP-sensitive potassium channel of rat pancreatic B cells recorded hy K. Gillis, L. Falke, and S. Misler. At the bottom, one opening is shown at finer time resolution to illustrate that it has self-similar fractal properties. (Reproduced with permission from reference 38.

The drug works by inhibiting the sulfonylurea receptor 1 (SURl), the regulatory subunit of the ATP-sensitive potassium channels (K p) pancreatic beta cells. This inhibition causes cell membrane depolarization opening voltage-dependent calcium channel. This results in an increase in intracellular calcium in the beta cell and subsequent stimulation of insulin release. 

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