Torsadogenic Cardiotoxicity of Antipsychotic Drugs: a Structural Feature, Potentially Involved in the Interaction with Cardiac HERG Potassium Channels

Abstract

Many non-cardiovascular drugs of common clinical use cause, as an unwanted accessory property, the prolongation of the cardiac repolarisation process, due to the block of the HERG (Human Ether-a-go-go Related Gene) potassium channel, responsible for the repolarising I(Kr) current. This delayed cardiac repolarisation process can be often unmasked by a prolongation of the QT interval of the ECG. In these conditions, premature action potentials can generate morphologically anomalous after-polarisations, and trigger a dangerous kind of polymorphic ventricular tachyarrhythmia, known as torsade de pointes, which can evolve in ventricular fibrillation and death. The risk associated with the torsadogenic cardiotoxicity of drugs, which prolong the QT interval has been the topic of documents produced by many health authorities, giving important issues about the preclinical and clinical evaluation of cardiac safety. Besides, public and private research laboratories developed several experimental in vitro or in vivo strategies, aimed to an early recognition of the influence of a drug (or of a drug-candidate) on the HERG channel and/or on the cardiac repolarisation process. Also the identification of a possible pharmacophore model, common in all or at least in numerous torsadogenic drugs, could represent a first step for the development of useful in silico approaches, allowing a preliminary indication about the potential torsadogenic property of a given molecule. In this work, we described the electrophysiological basis of torsade de pointes and listed several pharmacological classes of torsadogenic drugs. Among them, we focused our attention on antipsychotics, with an accurate overview on the experimental and clinical reports about their torsadogenic properties. Moreover, a common structural feature exhibited by these drugs, despite of their remarkable chemical differences, is evidenced by a computational approach and is indicated as a possible "facilitating" requirement for their torsadogenic properties. Together with other remarks, coming from different computational studies, the individuation of a satisfactory "toxicophore" model could be greatly useful, for the theoretical prediction of torsadogenic properties of a given chemical moiety and for the design of new drugs devoid of such an undesired and potentially lethal side-effect.

Discovery of Tetrasubstituted Imidazolines as Potent and Selective Neuropeptide Y Y5 Receptor Antagonists: Reduced Human Ether-a-go-go Related Gene Potassium Channel Binding Affinity and Potent Antiobesity Effect

“…After oral administration, compound 1b was shown to inhibit food intake in rats induced by centrally administered Y5-preferring agonist, NPY, where the minimum effective dose of 1b was 30 mg/kg. 13 Further investigation of leads 1a and 1b was necessary to address issues such as moderate in vivo potency and potent human ether-a-go-go related gene potassium channel (hERG) inhibitory activity 14 in order to identify clinical candidates from this class (Table 1). In this report, compounds 1a and 1b were further optimized by modification of the 2, 4, and 5-positions of the imidazoline substituents, resulting in the identification of a potent and selective derivative, 2a.…”

Block of Delayed-Rectifier Potassium Channels by Reduced Haloperidol and Related Compounds in Mouse Cortical Neurons

“…Nevertheless, the binding affinities to the K DR channel of both R-haloperidol and haloperidol were comparable. It is likely the role of carbonyl oxygen was overestimated in the above-mentioned in silico study (Testai et al, 2004).…”

“…The oxygen atom in the carbonyl group has been proposed to involve the binding of haloperidol to the central cavity of HERG channels in an in silico study (Testai et al, 2004). Most compounds listed in that study have already been reported as blockers for other potassium channels, including K DR channels.…”

“…Conversely, acute application of haloperidol has been reported to block numerous types of ion channels, including ATP-sensitive potassium channel (Yang et al, 2004), G protein-activated inwardly rectifying potassium channel (Kobayashi et al, 2000), and human ether-a-go-go-related gene (HERG) potassium channels (Shuba et al, 2001). Drug-induced torsade de pointes, a lethal type of cardiac arrhythmia, has been correlated with blocking of the HERG channel by certain compounds, including haloperidol (Brown et al, 2004;Testai et al, 2004). Therefore, understanding the basic mechanism of drug-channel interaction may provide useful information for structure-based drug design (Fermini and Fossa, 2003).…”

“…Aberrant activity of potassium channels has been shown in pathophysiological conditions, such as neurologic disorders, cardiac arrhythmia, and diabetes (Shieh et al, 2000). Therefore, the therapeutic and toxicologic aspects of drug-induced alterations in potassium channel activity are particularly relevant (Fermini and Fossa, 2003;Testai et al, 2004). Slow opening and lack of a fast inactivation process characterize delayed-rectifier potassium channels (K DR ).…”