QT Prolongation Through hERG K<sup>+</sup> Channel Blockade: Current Knowledge and Strategies for the Early Prediction During Drug Development

Recanatini, Maurizio; Poluzzi, Elisabetta; Masetti, Matteo; Cavalli, Andrea; Ponti, Fabrizio De

doi:10.1002/chin.200524263

Cited by 72 publications

(120 citation statements)

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“…Tricyclic antidepressants are known for their ability to cause sudden cardiac death in higher chronic dosages or, especially, in case of accidental or suicidal overdoses (Ray et al, 2004). This side effect is caused by inhibition of the hERG potassium channel and subsequent prolongation of the QT interval (Recanatini et al, 2005;Song and Clark, 2006). However, no hERG inhibition up to 10 mM could be detected for N-Desalkylquetiapine in the screening, suggesting that N-Desalkylquetiapine might be free of cardiovascular liability.…”

Section: Critical Off-target Activitiesmentioning

confidence: 99%

N-Desalkylquetiapine, a Potent Norepinephrine Reuptake Inhibitor and Partial 5-HT1A Agonist, as a Putative Mediator of Quetiapine's Antidepressant Activity

Jensen

Rodriguiz

Caron

et al. 2007

Neuropsychopharmacol

269

219

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Quetiapine is an atypical antipsychotic drug that is also US FDA approved for treating bipolar depression, albeit by an unknown mechanism. To discover the potential mechanism for this apparently unique action, we screened quetiapine, its metabolite N-Desalkylquetiapine, and dibenzo [b,f][1,4]thiazepine-11(10-H)-one (DBTO) against a large panel of G-protein-coupled receptors, ion channels, and neurotransmitter transporters. DBTO was inactive at all tested molecular targets. N-Desalkylquetiapine had a high affinity (3.4 nM) for the histamine H 1 receptor and moderate affinities (10-100 nM) for the norepinephrine reuptake transporter (NET), the serotonin 5-HT 1A , 5-HT 1E , 5-HT 2A , 5-HT 2B , 5-HT 7 receptors, the a 1B -adrenergic receptor, and the M 1 , M 3 , and M 5 muscarinic receptors. The compound had low affinities (100-1000 nM) for the 5-HT 1D , 5-HT 2C , 5-HT 3 , 5-HT 5 , 5-HT 6 , a 1A , a 2A , a 2B , a 2C , H 2 , M 2 , M 4 , and dopamine D 1 , D 2 , D 3 , and D 4 receptors. N-Desalkylquetiapine potently inhibited human NE transporter with a K i of 12 nM, about 100-fold more potent than quetiapine itself. N-Desalkylquetiapine was also 10-fold more potent and more efficacious than quetiapine at the 5-HT 1A receptor. N-Desalkylquetiapine was an antagonist at 5-HT 2A , 5-HT 2B , 5-HT 2C , a 1A , a 1D , a 2A , a 2C , H 1 , M 1 , M 3 , and M 5 receptors. In the mouse tail suspension test, N-Desalkylquetiapine displayed potent antidepressant-like activity in VMAT2 heterozygous mice at doses as low as 0.1 mg/kg. These data strongly suggest that the antidepressant activity of quetiapine is mediated, at least in part, by its metabolite N-Desalkylquetiapine through NET inhibition and partial 5-HT 1A agonism. Possible contributions of this metabolite to the side effects of quetiapine are discussed.

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Section: Critical Off-target Activitiesmentioning

confidence: 99%

N-Desalkylquetiapine, a Potent Norepinephrine Reuptake Inhibitor and Partial 5-HT1A Agonist, as a Putative Mediator of Quetiapine's Antidepressant Activity

Jensen

Rodriguiz

Caron

et al. 2007

Neuropsychopharmacol

269

219

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“…The promiscuous inhibition of hERG channels by a variety of chemical structures 36,38 and the high hit rate for hERG inhibitors observed in the Tl þ assay favor the idea of focusing the analyses of effects in the IonWorks assay to data obtained at 1 mM compound concentration. The duplicate tests of 1,999 compounds yielded 1,373 pairs of data points from two repeats of separate plates, representing an average of 86% success rate of electrophysiological recording per plate.…”

Section: Ionwork-based Electrophysiological Assaymentioning

confidence: 99%

Profiling Diverse Compounds by Flux- and Electrophysiology-Based Primary Screens for Inhibition of Human Ether-à-go-go Related Gene Potassium Channels

Zou

Babcock

et al. 2010

ASSAY and Drug Development Technologies

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Compound effects on cloned human Ether-à-go-go related gene (hERG) potassium channels have been used to assess the potential cardiac safety liabilities of drug development candidate compounds. In addition to radioactive ligand displacement tests, two other common approaches are surrogate ion-based flux assays and electrophysiological recordings. The former has much higher throughput, whereas the latter measures directly the effects on ionic currents. Careful characterization in earlier reports has been performed to compare the relative effectiveness of these approaches for known hERG blockers, which often yielded good overall correlation. However, cases were reported showing significant and reproducible differences in potency and/or sensitivity by the two methods. This raises a question concerning the rationale and criteria on which an assay should be selected for evaluating unknown compounds. To provide a general basis for considering assays to profile large compound libraries for hERG activity, we have conducted parallel flux and electrophysiological analyses of 2,000 diverse compounds, representative of the 300,000 compound collection of NIH Molecular Library Small Molecular Repository (MLSMR). Our results indicate that at the conventional testing concentration 1.0 mM, the overlap between the two assays ranges from 32% to 50% depending on the hit selection criteria. There was a noticeable rate of false negatives by the thallium-based assay relative to electrophysiological recording, which may be greatly reduced under modified comparative conditions. As these statistical results identify a preferred method for cardiac safety profiling of unknown compounds, they suggest an efficient method combining flux and electrophysiological assays to rapidly profile hERG liabilities of large collection of naive compounds.

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“…The potential of a drug to cause QT prolongation has been a commonly cited reason for the withdrawal of medications from the pharmaceutical market. As a result, compounds are now subjected to time consuming and expensive screening procedures during development (Fermini and Fossa, 2003;Recanatini et al, 2004). An accurate understanding of the molecular basis of drug binding to hERG would significantly facilitate the development and safety profile of new medications (Sanguinetti and Mitcheson, 2005).…”

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confidence: 99%

Drug Binding Interactions in the Inner Cavity of hERG Channels: Molecular Insights from Structure-Activity Relationships of Clofilium and Ibutilide Analogs

Perry¹,

Stansfeld²,

Leaney³

et al. 2005

Mol Pharmacol

103

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Block of human ether-a-go-go related gene (hERG) Kϩ channels by otherwise useful drugs is the most common cause of long QT syndrome, a disorder of cardiac repolarization that predisposes patients to potentially fatal arrhythmias. This undesirable long QT side effect has been a major reason for the withdrawal of medications from the pharmaceutical market. Understanding the molecular basis of hERG block is therefore essential to facilitate the design of safe drugs. Binding sites for hERG blockers have been mapped within the inner cavity of the channel and include aromatic residues in the S6 helix (Tyr-652, Phe-656) and residues in the pore helix (Thr-623, Ser-624, Val-625). We used mutagenesis of these residues, combined with an investigation of hERG block by close analogs of clofilium and ibutilide, to assess how specific alterations in drug structure affected potency and binding interactions. Although changing the basic nitrogen from quaternary to tertiary accelerated the onset of block, the IC 50 and kinetics for recovery from block were similar. In contrast, analogs with different para-substituents on the phenyl ring had significantly different potencies for wild-type hERG block. The highest potency was achieved with polar or electronegative para-substituents, whereas neutral para-substituents had potencies more than 100-fold lower. Results from mutagenesis and molecular modeling studies suggest that phenyl ring para-substituents influence drug interactions with Thr-623, Ser-624, and Tyr-652 and strongly affect binding affinity. Together, these findings suggest that modifying the para-substituent could be a useful strategy for reducing hERG potency and increasing the safety margin of compounds in development.

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QT Prolongation Through hERG K⁺ Channel Blockade: Current Knowledge and Strategies for the Early Prediction During Drug Development

Abstract: RECANATINI*, M.; POLUZZI, E.; MASETTI, M.; CAVALLI, A.; DE PONTI, F.; Med. Res. Rev. 25 (2005) 2, 133-166; Dip. Sci. Farm., Univ. Bologna, I-40126 Bologna, Italy; Eng.) -Lindner 24-263

Cited by 72 publications

References 1 publication

N-Desalkylquetiapine, a Potent Norepinephrine Reuptake Inhibitor and Partial 5-HT1A Agonist, as a Putative Mediator of Quetiapine's Antidepressant Activity

N-Desalkylquetiapine, a Potent Norepinephrine Reuptake Inhibitor and Partial 5-HT1A Agonist, as a Putative Mediator of Quetiapine's Antidepressant Activity

Profiling Diverse Compounds by Flux- and Electrophysiology-Based Primary Screens for Inhibition of Human Ether-à-go-go Related Gene Potassium Channels

Drug Binding Interactions in the Inner Cavity of hERG Channels: Molecular Insights from Structure-Activity Relationships of Clofilium and Ibutilide Analogs

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QT Prolongation Through hERG K+ Channel Blockade: Current Knowledge and Strategies for the Early Prediction During Drug Development

Abstract: RECANATINI*, M.; POLUZZI, E.; MASETTI, M.; CAVALLI, A.; DE PONTI, F.; Med. Res. Rev. 25 (2005) 2, 133-166; Dip. Sci. Farm., Univ. Bologna, I-40126 Bologna, Italy; Eng.) -Lindner 24-263

Cited by 72 publications

References 1 publication

N-Desalkylquetiapine, a Potent Norepinephrine Reuptake Inhibitor and Partial 5-HT1A Agonist, as a Putative Mediator of Quetiapine's Antidepressant Activity

N-Desalkylquetiapine, a Potent Norepinephrine Reuptake Inhibitor and Partial 5-HT1A Agonist, as a Putative Mediator of Quetiapine's Antidepressant Activity

Profiling Diverse Compounds by Flux- and Electrophysiology-Based Primary Screens for Inhibition of Human Ether-à-go-go Related Gene Potassium Channels

Drug Binding Interactions in the Inner Cavity of hERG Channels: Molecular Insights from Structure-Activity Relationships of Clofilium and Ibutilide Analogs

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QT Prolongation Through hERG K⁺ Channel Blockade: Current Knowledge and Strategies for the Early Prediction During Drug Development