Potassium-channel blockers

Another, as yet experimental use of sulfonylurea derivatives targets the Kj, channels in the heart in certain forms of arrhythmias. The sulfonylurea receptors in the heart are somewhat different from those in the (3-cells, which makes selective drug action possible. Closing potassium channels should increase the excitability of heart muscle cells - in contrast to the effect of sodium (and calcium) channel blockers Don t worry, though - the cardiologists will find a way to show us why this is a good thing, like old farm- 

---

Packed column SFC has also been applied to preparative-scale separations [42], In comparison to preparative LC, SFC offers reduced solvent consumption and easier product recovery [43]. Whatley [44] described the preparative-scale resolution of potassium channel blockers. Increased resolution in SFC improved peak symmetry and allowed higher sample throughput when compared to LC. The enhanced resolution obtained in SFC also increases the enantiomeric purity of the fractions collected. Currently, the major obstacle to widespread use of preparative SFC has been the cost and complexity of the instrumentation. 

G, Jiang H, Chen K. Structure-based discovery of potassium channel blockers from natural products virtual screening and electrophysiological assay testing. Chem Biol 2003 10 1103-13. 

Sodium channel blockers p-adrenergic blockers Potassium channel blockers Calcium channel blockers Adenosine Digoxin... 

Cianchetta, G., Li, Y., Kang, J., Rampe, D., Fravolini, A., Crudani, G. and Vaz, R.J. (2005) Predictive models for hERG potassium channel blockers. Bioorganic el Medicinal Chemistry Letters, 15, 3637-3642. 

Crossley R, Opalko A. (1996) The structure-activity relationships of potassium channel Blockers, in JM Evans, et al. (eds). Potassium Channels and their Modulators, Taylor and Francis. 

Mechanism of Action A selective potassium channel blocker that prolongs repolar-ization without affecting conduction velocity by blocking one or more time-dependent potassium currents. Dofetilide has no effect on sodium channels or adrenergic alpha or beta receptors. Therapeutic Effect Terminates reentrant tachyarrhythmias,... 

Ibutilide Potassium channel blocker, may activate inward current IV use for conversion in atrial flutter and fibrillation... 

Ocana, M., Del Pozo, E., Barrios, M., Robles, L. I., Baeyens, J. M. An ATP-dependent potassium channel blocker antagonizes morphine analgesia, European Journal of Pharmacology 1990, 186, 377-378. 

Scientists at Merck have reported a number of biocatalytic routes derived from screening various microorganisms targeted to produce key intermediates that are then combined with chemical reactions to prepare the target molecule. The biocatalytic step was often carried out by necessity as a result of poor chemical yield, low optical purity, or both. 6-Bromo-P-tetralone (2) was reduced to (S)-6-bromo-P-tetralol (3) by the yeast Trichosporon capitatum MY 1890 (Scheme 19.6).79 The tetralol 3 is a key intermediate for the synthesis of MK-0499 (4), a potassium channel blocker. The (S)-P-tetralol 3 was produced in gram quantities with an ee of >99% to support further development of MK-0499. Baker s yeast was tested for its ability to carry out this reduction but showed insignificant product formation. 

Abdul M, Santo A, Hoosein N (2003) Activity of potassium channel-blockers in breast cancer. Anticancer Res 23 3347-3351... 

Two interesting examples are found in cyclic analogues of / -blockers (Fig. 1.9). Cydization to the morpholine yields the antidepressant viloxazine (mode 1), whereas cydization to chromanols (mode 2) yields the potassium channel blocker cromakalim. 

Fig. 1.9 Two modes of cydization of the side chain in -blockers yield the noradrenaline (NA) reuptake inhibitor viloxazine (mode 1) and the potassium channel blocker cromakalim (mode 2).

Cass WA, Zahniser NR (1991) Potassium channel blockers inhibit D2 dopamine, but not A1 adenosine, receptor-mediated inhibition of striatal dopamine release. J Neurochem 57 147-152. 

Another facet of striatal LTP is that potentiation is reliably induced by HFS in the presence of the potassium-channel blocker, tetra-ethyl ammonium (Walsh, 1991 Wickens et al., 1998). By analogy with other systems, this result might be interpreted as an increased influx of calcium into the postsynaptic neuron. However, this does not appear to be the case. Intracellular application of potassium-channel blockers does not facilitate LTP (Wickens et al., 1998), as would be predicted, if these effects were mediated by greater depolarization of the postsynaptic neuron. The facilitation of LTP by extracellular potassium-channel blockers is therefore more likely to be due to presynaptic effects, such as facilitation of dopamine release by prolongation of the action potential in dopaminergic axon terminals. 

Wickens JR, Mckenzie D, Constanzo E, Arbuthnott GW (1998) Site of action of potassium channel blockers in striatal long-term potentiation. Neuropharmacol 57 523-533. 

Table 1 Selected Step 6 experimental derivatives and accompanying mass spectra data and Kvl.5 channel inhibition concentration, IC50. H NMR for all entries supplied by the author. Entries 1, 13, 19, and 27 are especially preferred as potassium channel blockers of the Kvl.5 channel...

B. Ultrarapidly Activating Potassium Channel Blockers of the Kvl.5 Channel... 

To address this concern, Kvl.5 potassium channel blockers have been prepared that ultrarapidly activate delayed rectifiers and inhibit a designated potassium current in the human atrium without increased susceptibility of new fibrillation events. 

Table 3 Selected thiophen-3-yl-benzylcarbamate derivatives and their corresponding mass spectral characterization data. All derivatives were effective as antiarrhythmic potassium channel blocker agents...

Table 4 Selected experimental agents effective as antiarrhythmic potassium channel blockers and corresponding IC50 values...

---