Pharmacological Removal of Human Ether-à-go-go-Related Gene Potassium Channel Inactivation by 3-Nitro-N-(4-phenoxyphenyl) Benzamide (ICA-105574)

@article{Gerlach2010PharmacologicalRO,
  title={Pharmacological Removal of Human Ether-{\`a}-go-go-Related Gene Potassium Channel Inactivation by 3-Nitro-N-(4-phenoxyphenyl) Benzamide (ICA-105574)},
  author={Aaron C. Gerlach and Sally Jo Stoehr and Neil A Castle},
  journal={Molecular Pharmacology},
  year={2010},
  volume={77},
  pages={58 - 68}
}
Human ether-à-go-go-related gene (hERG) potassium channel activity helps shape the cardiac action potential and influences its duration. In this study, we report the discovery of 3-nitro-N-(4-phenoxyphenyl) benzamide (ICA-105574), a potent and efficacious hERG channel activator with a unique mechanism of action. In whole-cell patch-clamp studies of recombinant hERG channels, ICA-105574 steeply potentiated current amplitudes more than 10-fold with an EC50 value of 0.5 ± 0.1 μM and a Hill slope… 

Figures from this paper

Molecular Determinants for Activation of Human Ether-à-go-go-related Gene 1 Potassium Channels by 3-Nitro-N-(4-phenoxyphenyl) Benzamide
TLDR
Findings indicate that ICA is a mixed agonist of hERG1 channels, and the addition of the F557L mutation rendered the channel drug-insensitive.
Molecular Determinants of Human ether-à-go-go-Related Gene 1 (hERG1) K+ Channel Activation by NS1643
TLDR
Scanning mutagenesis of hERG1 and functional characterization of 56 mutant channels heterologously expressed in Xenopus laevis oocytes are used to define the molecular determinants of the binding site for 1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643), a compound that increases hERG 1 currents by shifting the voltage-dependence of inactivation to more positive potentials.
Blockade of the Human Ether A-Go-Go–Related Gene (hERG) Potassium Channel by Fentanyl
TLDR
Although mechanisms of fentanyl-related sudden death need further investigation, blockade of hERG channels may contribute to the death of individuals with high-concentration overdose or compromised cardiac repolarization.
Strong Activation of ether-à-go-go-Related Gene 1 K+ Channel Isoforms by NS1643 in Human Embryonic Kidney 293 and Chinese Hamster Ovary Cells
TLDR
It is noteworthy that rerg1b and herg1a inactivation estimated from fully activated current voltage relationships were unaltered in the continued presence of 10 μM NS16 43 in the mammalian expression systems, indicating qualitative differences from NS1643 effects in X. laevis oocytes.
The Human Ether-a-go-go-related Gene (hERG) Potassium Channel Represents an Unusual Target for Protease-mediated Damage*
TLDR
It is demonstrated that the hERG/IKr channel was selectively cleaved by the serine protease, proteinase K (PK), and it was found that calpain-1 was actively released into the extracellular milieu and cleaved hERG at the S5-pore linker of hERG.
Concatenated hERG1 Tetramers Reveal Stoichiometry of Altered Channel Gating by RPR-260243
TLDR
These findings suggest that the allosteric modulation of channel gating involves distinct mechanisms of coupling between drug binding and altered deactivation and inactivation, and may facilitate the design of more selective and potent compounds for prevention of arrhythmia associated with abnormally prolonged ventricular repolarization.
Activation of human ether-a-go-go related gene (hERG) potassium channels by small molecules
TLDR
The aim of this review is to discuss recent advances concerning the identification and action mechanism of hERG activators.
Toward a Structural View of hERG Activation by the Small-Molecule Activator ICA-105574
TLDR
The findings indicate that ICA increases the stability of the SF to attenuate channel inactivation, and this action requires a fine-tuned compound geometry.
Tuning of EAG K+ channel inactivation: Molecular determinants of amplification by mutations and a small molecule
TLDR
It is shown that human EAG1 channels exhibit an intrinsic voltage-dependent slow inactivation that is markedly enhanced in rate and extent by 1–10 µM 3-nitro-N-(4-phenoxyphenyl) benzamide, or ICA105574 (ICA).
...
...

References

SHOWING 1-10 OF 36 REFERENCES
Structural basis of action for a human ether-a-go-go-related gene 1 potassium channel activator
TLDR
A putative binding site for RPR is defined and the importance of an interaction between the S4–S5 linker and the S6 domain in electromechanical coupling of voltage-gated K+ channels is confirmed.
Biophysical Characterization of the New Human Ether-A-Go-Go-Related Gene Channel Opener NS3623 [N-(4-Bromo-2-(1H-tetrazol-5-yl)-phenyl)-N′-(3′-trifluoromethylphenyl)urea]
TLDR
It is concluded that NS3623 has a dual mode of action, being both an activator and an inhibitor of HERG1 channels and has the ability to shorten action potential durations in guinea pig papillary muscle.
Activation of Human ether-a-go-go-Related Gene Potassium Channels by the Diphenylurea 1,3-Bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643)
TLDR
HerG channel activation by small molecules such as NS1643 increases the repolarization reserve and presents an interesting new antiarrhythmic approach.
Discovery of a Small Molecule Activator of the Human Ether-a-go-go-Related Gene (HERG) Cardiac K+ Channel
TLDR
It is believed that RPR260243 represents the first known HERG channel activator and that the drug works primarily by inhibiting channel closure, leading to a persistent HerG channel current upon repolarization.
Novel Potent Human Ether-à-Go-Go-Related Gene (hERG) Potassium Channel Enhancers and Their in Vitro Antiarrhythmic Activity
TLDR
The data support the notion that hERG activation by pharmaceuticals may offer a new approach in the treatment of delayed repolarization conditions, which may occur in patients with inherited or acquired long QT syndrome, congestive heart failure, and diabetes.
Probing the Binding Sites and Mechanisms of Action of Two Human Ether-a-go-go-Related Gene Channel Activators, 1,3-bis-(2-Hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643) and 2-[2-(3,4-Dichloro-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-nicotinic acid (PD307243)
TLDR
It is suggested that PD may work as a “pore-modifier” of the hERG channel: it binds to the outer vestibule/pore entrance of hERG and increases current amplitudes by promoting channel activation while retarding inactivation.
Mechanism of Action of a Novel Human ether-a-go-go-Related Gene Channel Activator
TLDR
It is concluded that NS1643 is a partial agonist of hERG channels and that the mechanism of activation is reduced channel inactivation.
2-[2-(3,4-Dichloro-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-nicotinic Acid (PD-307243) Causes Instantaneous Current through Human Ether-a-go-go-Related Gene Potassium Channels
TLDR
Docking studies suggest that PD-307243 interacts with residues in the S5-P region of the channel, which is similar to those observed in hERG channel-transfected CHO cells.
Mallotoxin Is a Novel Human Ether-a-go-go-Related Gene (hERG) Potassium Channel Activator
TLDR
A novel, naturally occurring hERG channel activator, mallotoxin (MTX), is described, which activates hERG channels through distinct mechanisms and with significantly higher potency than previously reported hERGChannel activators.
Electrophysiologic characterization of a novel hERG channel activator.
...
...