HERG-channels

In general, the detection of adverse drug reactions early in the drug discovery process is becoming commonplace. So-called liability panels of receptors, hERG channel activity, and cytochrome enzymes are utilized to identify... 

A particularly interesting example of Kv-channel inactivation is represented by HERG-channels. HERG-channels have faster inactivation than activation kinetics, and they very rapidly recover from inactivation at negative membrane potentials. This behavior may result in a situation where most of the current carried by HERG-channels occurs during their recovery from inactivation at negative potentials, that is, it represents an inward rather than outward current. 

KCNQ-channels, HERG-channels, and Shaker-related Kv-channels. 

Heparin Sulfate Proteoglycans Hepatic Lipase Hepatitis Hepatitis C Heptahelical Domain Heptahelical Receptors HERG-channels Heterologous Desensitization Heterologous Expression System Heterotrimeric G-Proteins Hidden Markov Model High-density Lipoprotein (HDL)... 

Fig. 12.5 Key elements of hERG channel topology are schematically illustrated using one subunit of the X-ray structure of bacterial KvAP [17], A hERG blocker is represented according to published evidence [1 7]. The...

Aronov, A. M. Predictive in silica modeling for hERG channel blockers. Drug Discov. Today 2005, 10,149-155. 

Inhibition of the hERG ion channel is firmly associated with cardiovascular toxicity in humans, and several drugs with this liability have been withdrawn. A number of studies show that basicity, lipophilicity, and the presence of aromatic rings [76] contribute to hERG binding. The 3D models of the hERG channel [77] are potentially useful to understand more subtle structure-activity relationships. In common with receptor promiscuity, both phospholipidosis and hERG inhibition are predominantly issues with lipophilic, basic compounds, and with the predictive models available, both risks should be well controlled. 

HERG channel interactions (HERG expressed in HEK 293 cells)... 

Aronov, A.M. (2005) Predictive in silico modeling for hERG channel blockers. Drug Discovery Today, 10, 149-155. 

However, it is important to recognize that (a) there are some h E RG blockers that are unlikely to cause TdP and (b) not only blockade, but also interference with the processing of mature hERG channels can lead to QT liability. 

Mammalian cell lines are the ideal model for studying an effect on the current underlying fKii they allow to use physiological temperatures (37 °C) for the human species HER 293, CHO or L cells expressing hERG channels may be used as a primary test to study the pharmacological activity of a compound... 

Inhibition of [3H]-dofetilide binding to hERG channels has also been proposed, but this nonfunctional assay has important limitations... 

In conclusion, QT prolongation by hERG channel blockers is per se dose dependent, whereas actual occurrence of TdP depends on the repolarization reserve, which is variable among subjects and over time. The exception to the mle are those hERG blockers with multiple, sometimes complementary electrophysiological actions, which lead to a bell-shaped concentration-response curve [109]. 

A recent study determined the myocardium to plasma concentration ratios of five antipsychotics and underscored the importance of interpreting hERG channel and electrophysiological data in conjunction with other pharmacokinetic parameters [114]. 

Finally, it is important to remember that, in case of racemic drugs, it is important to resort to stereoselective methods to detect possible differences in the actions of the test compounds at the desired target and hERG channels. For instance, a recent study detected differences between (R)- and (S)-methadone [115]. 

Shao, X.D., Wu, K.C., Hao, Z.M., Hong, L., Zhang, J. and Fan, D.M. (2005) The potent inhibitory effects of cisapride, a specific blocker for human efher-a-go-go-related gene (HERG) channel, on gastric cancer cells. Cancer Biology e[ Therapy, 4, 295-301. 

Suessbrich, H., Waldegger, S., Lang, F. and Busch, A.E. (1996) Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and astemizole. FEBS Letters, 385, 77-80. 

Siebrands, C.C., Schmitt, N. and Friederich, P. (2005) Local anesthetic interaction with human ether-a-go-go-related gene (HERG) channels role of aromatic amino acids Y652 and F656. Anesthesiology, 103, 102-112. 

Luck, S., Kiesecker, C., Thomas, D., Kathofer, S., Niroomand, F., Kiehn, J., Kreye, V.A., Katus, H.A., Schoels, W. and Karle, C.A. (2005) QTc prolongation by grapefruit juice and its potential pharmacological basis HERG channel blockade by flavonoids. Circulation, 111, 835-838. 

Mitcheson, J.S. (2003) Drug binding to HERG channels evidence for a nonaromatic binding site for fluvoxamine. British Journal of Pharmacology, 139, 883-884. 

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