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Ion Channels in Human Pluripotent Stem Cells and Their Neural Derivatives
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Ritika Raghavan, Robert Juniewicz, Maharaib Syed, Michael Lin, Peng Jiang
Interestingly, human ether-a-go-go (hERG) channels (voltage-dependent K+ channels) were only found to be in hESCs, but not in hiPSCs (33,34). In addition, hyperpolarization-activated pacemaker currents (If) were detected in hESCs, but were absent in hiPSCs. hERG channel-mediated K+ currents and If are known to be important for cardiomyocyte development and functions (35,36). The differences in the expression of these ion channels in hESCs and hiPSCs may affect their differentiation to cardiac cell lineages (37,38).
Medicinal poisons
Published in Jason Payne-James, Richard Jones, Simpson's Forensic Medicine, 2019
Jason Payne-James, Richard Jones
Some individuals carry mutations that make them more subject to hERG interactions. The end result is the same as with any hereditary cause of the disease: QT prolongation, arrhythmia and sudden death. Methadone is perhaps the most notorious of the drugs that produces this syndrome but, as indicated in Box 25.2, the list of drugs is a long one and is growing continuously. Routine toxicology screening will not reveal whether this interaction has occurred, and there will be no detectable changes at autopsy, making a thorough review of the medical history mandatory; even then the diagnosis may be impossible to make at autopsy.
Nonclinical Safety Evaluation of Drugs
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Thomas M. Monticello, Jeanine L. Bussiere
Cardiac arrhythmias, such as Torsades de pointes (TdP), is a specific and rare variety of ventricular tachycardia that can progress to ventricular fibrillation. Prolongation of the QT interval, observed on an electrocardiogram (ECG), precedes the onset of this serious and often life-threatening arrhythmia. A common cause of long QT syndrome is a block of the hERG (human ether-a-go-go-related gene) ion channel. The hERG ion channel is a major contributor to cardiac repolarization and several marketed drugs have been reported to block the hERG channel, resulting in acquired long QT syndrome and TdP (Redfern et al. 2002; Roden 1998). The potential for drug-induced hERG binding, therefore, is now routinely evaluated and screened in a high-throughput assay during lead optimization (Bowlby et al. 2008).
N-Methyl-D-Aspartate (NMDA) receptor modulators: a patent review (2015-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Hazem Ahmed, Ahmed Haider, Simon M. Ametamey
Six patents were filed by Janssen Pharmaceutica claiming 639 substituted 4-azaindole derivatives, 111 pyrazole derivatives, 118 triazole derivatives, another 716 triazole derivatives, 612 imidazopyridine derivatives, and 203 pyridine/pyrimidine derivatives as GluN1/GluN2B modulators [162–167]. For the substituted 4-azaindole derivatives patent, general synthetic procedures, mass spectroscopy, and proton NMR data of all the compounds were included [162]. The binding affinities of all the compounds toward GluN2B subunit-containing NMDA receptors were assayed using cortical rat brain membranes, and 3-[3H]-1-(azetidin-1-yl)-2[6-(4-fluoro-3-methyl-phenyl)pyrrolo[3,2-b]pyridine-1-yl]ethanone as the radioligand in a competitive binding experiment. In vitro efficacy values, on the other hand, were recorded via a cell-based calcium flux test, where the cells were of mammalian origin, and expressing cloned human GluN1/GluN2B ion channels. pIC50 values were listed for all the compounds with 8.7 being the highest for a deuterated 4-azaindole derivative. For pyrazole derivatives, IC50 values were provided for 105 compounds as determined from competitive binding assays using [3H]ifenprodil and rat brain homogenates [163]. Only three compounds exhibited one digit nanomolar IC50 values. This patent additionally provided information on GluN1/GluN2B antagonistic activity against the positive control, dizocilpine, with values ranging between 0.23 and 59.7 µM. The hERG potassium channel inhibition test was also performed as a potential cardiotoxicity indicator.
Utilizing postmortem drug concentrations in mechanistic modeling and simulation of cardiac effects: a proof of concept study with methadone
Published in Toxicology Mechanisms and Methods, 2018
Christian Reuss Mikkelsen, Jakob Ross Jornil, Ljubica Vukelic Andersen, Jørgen Bo Hasselstrøm, Sebastian Polak
The cause of death behind methadone intoxication may be respiratory depression (Corkery et al. 2004). Conversely, methadone is also a known inhibitor of the human ether-a-go-go-related gene (hERG) potassium channel (Katchman et al. 2002; Eap et al. 2007). hERG inhibition is involved in the prolongation of the QT-interval, which may develop into the ventricular arrhythmia ‘Torsades de Pointes’ (TdP) and possibly sudden cardiac death (SCD) (Testai et al. 2004). Methadone has been associated with heart rate-corrected QT-interval (QTc) prolongation, and QTc-prolongation has been correlated with either dose (Kornick et al. 2003; Fanoe et al. 2007) or plasma concentration (Martell et al. 2005; Skjervold et al. 2006; Eap et al. 2007; Peles et al. 2007). Furthermore, TdP has also been reported in methadone-treated patients (Krantz et al. 2002; De Bels et al. 2003; Ehret et al. 2006). Therefore, aside from respiratory depression, methadone may cause SCD.
Binding modes of hERG blockers: an unsolved mystery in the drug design arena
Published in Expert Opinion on Drug Discovery, 2018
Subha Kalyaanamoorthy, Khaled H. Barakat
Resolving the experimental structures of the hERG channel represents a significant milestone toward understanding their molecular function and their unusual promiscuity to bind a wide range of drugs. The structural features identified from the cryo-structure spawns several additional questions that should stimulate future research for better understanding of the hERG channels’ drug-binding aspect. Since the structure was resolved without a bound ligand, the prime question of how and where the drug binds is still open. In addition to this, the extended pockets identified in the structures raise questions about the possibility of this region to serve as a binding site. In order to find the suitability of the hydrophobic site for drug binding, it is necessary to know how stable are these pockets? And what happens to this site during repolarization, i.e. when the channel gates are closed?