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A new negative allosteric modulator, AP14145, for the study of small conductance calcium-activated potassium (K2) channels

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A new negative allosteric modulator, AP14145, for the study of small conductance calcium-activated potassium (K2) channels. / Simó-Vicens, Rafel; Kirchhoff, Jeppe E; Dolce, Bernardo; Abildgaard, Lea; Speerschneider, Tobias; Sørensen, Ulrik S; Grunnet, Morten; Diness, Jonas G; Bentzen, Bo H.

In: BRIT J PHARMACOL, Vol. 174, No. 23, 12.2017, p. 4396-4408.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Simó-Vicens, R, Kirchhoff, JE, Dolce, B, Abildgaard, L, Speerschneider, T, Sørensen, US, Grunnet, M, Diness, JG & Bentzen, BH 2017, 'A new negative allosteric modulator, AP14145, for the study of small conductance calcium-activated potassium (K2) channels', BRIT J PHARMACOL, vol. 174, no. 23, pp. 4396-4408. https://doi.org/10.1111/bph.14043

APA

Simó-Vicens, R., Kirchhoff, J. E., Dolce, B., Abildgaard, L., Speerschneider, T., Sørensen, U. S., Grunnet, M., Diness, J. G., & Bentzen, B. H. (2017). A new negative allosteric modulator, AP14145, for the study of small conductance calcium-activated potassium (K2) channels. BRIT J PHARMACOL, 174(23), 4396-4408. https://doi.org/10.1111/bph.14043

Vancouver

Simó-Vicens R, Kirchhoff JE, Dolce B, Abildgaard L, Speerschneider T, Sørensen US et al. A new negative allosteric modulator, AP14145, for the study of small conductance calcium-activated potassium (K2) channels. BRIT J PHARMACOL. 2017 Dec;174(23):4396-4408. https://doi.org/10.1111/bph.14043

Bibtex

@article{e50e2c0ca41a472eb93e487c32d4fc96,
title = "A new negative allosteric modulator, AP14145, for the study of small conductance calcium-activated potassium (K2) channels",
abstract = "BACKGROUND AND PURPOSE: Small conductance calcium-activated potassium (KCa2) channels represent a promising atrial-selective target for treatment of atrial fibrillation. Here, we establish the mechanism of KCa2 channel inhibition by the new compound AP14145.EXPERIMENTAL APPROACH: Using site-directed mutagenesis, binding determinants for AP14145 inhibition were explored. AP14145 selectivity and mechanism of action were investigated by patch-clamp recordings of heterologously expressed KCa2 channels. The biological efficacy of AP14145 was assessed by measuring atrial effective refractory period (AERP) prolongation in anaesthetized rats, and a beam walk test was performed in mice to determine acute CNS-related effects of the drug.KEY RESULTS: AP14145 was found to be an equipotent negative allosteric modulator of KCa2.2 and KCa2.3 channels (IC50 = 1.1 ± 0.3 μM). The presence of AP14145 (10 μM) increased the EC50of Ca2+on KCa2.3 channels from 0.36 ± 0.02 to 1.2 ± 0.1 μM. The inhibitory effect strongly depended on two amino acids, S508 and A533 in the channel. AP14145 concentration-dependently prolonged AERP in rats. Moreover, AP14145 (10 mg·kg-1) did not trigger any apparent CNS effects in mice.CONCLUSIONS AND IMPLICATIONS: AP14145 is a negative allosteric modulator of KCa2.2 and KCa2.3 channels that shifted the calcium dependence of channel activation, an effect strongly dependent on two identified amino acids. AP14145 prolonged AERP in rats and did not trigger any acute CNS effects in mice. The understanding of how KCa2 channels are inhibited, at the molecular level, will help further development of drugs targeting KCa2 channels.",
keywords = "Journal Article",
author = "Rafel Sim{\'o}-Vicens and Kirchhoff, {Jeppe E} and Bernardo Dolce and Lea Abildgaard and Tobias Speerschneider and S{\o}rensen, {Ulrik S} and Morten Grunnet and Diness, {Jonas G} and Bentzen, {Bo H}",
note = "{\textcopyright} 2017 The British Pharmacological Society.",
year = "2017",
month = dec,
doi = "10.1111/bph.14043",
language = "English",
volume = "174",
pages = "4396--4408",
journal = "BRIT J PHARMACOL",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "23",

}

RIS

TY - JOUR

T1 - A new negative allosteric modulator, AP14145, for the study of small conductance calcium-activated potassium (K2) channels

AU - Simó-Vicens, Rafel

AU - Kirchhoff, Jeppe E

AU - Dolce, Bernardo

AU - Abildgaard, Lea

AU - Speerschneider, Tobias

AU - Sørensen, Ulrik S

AU - Grunnet, Morten

AU - Diness, Jonas G

AU - Bentzen, Bo H

N1 - © 2017 The British Pharmacological Society.

PY - 2017/12

Y1 - 2017/12

N2 - BACKGROUND AND PURPOSE: Small conductance calcium-activated potassium (KCa2) channels represent a promising atrial-selective target for treatment of atrial fibrillation. Here, we establish the mechanism of KCa2 channel inhibition by the new compound AP14145.EXPERIMENTAL APPROACH: Using site-directed mutagenesis, binding determinants for AP14145 inhibition were explored. AP14145 selectivity and mechanism of action were investigated by patch-clamp recordings of heterologously expressed KCa2 channels. The biological efficacy of AP14145 was assessed by measuring atrial effective refractory period (AERP) prolongation in anaesthetized rats, and a beam walk test was performed in mice to determine acute CNS-related effects of the drug.KEY RESULTS: AP14145 was found to be an equipotent negative allosteric modulator of KCa2.2 and KCa2.3 channels (IC50 = 1.1 ± 0.3 μM). The presence of AP14145 (10 μM) increased the EC50of Ca2+on KCa2.3 channels from 0.36 ± 0.02 to 1.2 ± 0.1 μM. The inhibitory effect strongly depended on two amino acids, S508 and A533 in the channel. AP14145 concentration-dependently prolonged AERP in rats. Moreover, AP14145 (10 mg·kg-1) did not trigger any apparent CNS effects in mice.CONCLUSIONS AND IMPLICATIONS: AP14145 is a negative allosteric modulator of KCa2.2 and KCa2.3 channels that shifted the calcium dependence of channel activation, an effect strongly dependent on two identified amino acids. AP14145 prolonged AERP in rats and did not trigger any acute CNS effects in mice. The understanding of how KCa2 channels are inhibited, at the molecular level, will help further development of drugs targeting KCa2 channels.

AB - BACKGROUND AND PURPOSE: Small conductance calcium-activated potassium (KCa2) channels represent a promising atrial-selective target for treatment of atrial fibrillation. Here, we establish the mechanism of KCa2 channel inhibition by the new compound AP14145.EXPERIMENTAL APPROACH: Using site-directed mutagenesis, binding determinants for AP14145 inhibition were explored. AP14145 selectivity and mechanism of action were investigated by patch-clamp recordings of heterologously expressed KCa2 channels. The biological efficacy of AP14145 was assessed by measuring atrial effective refractory period (AERP) prolongation in anaesthetized rats, and a beam walk test was performed in mice to determine acute CNS-related effects of the drug.KEY RESULTS: AP14145 was found to be an equipotent negative allosteric modulator of KCa2.2 and KCa2.3 channels (IC50 = 1.1 ± 0.3 μM). The presence of AP14145 (10 μM) increased the EC50of Ca2+on KCa2.3 channels from 0.36 ± 0.02 to 1.2 ± 0.1 μM. The inhibitory effect strongly depended on two amino acids, S508 and A533 in the channel. AP14145 concentration-dependently prolonged AERP in rats. Moreover, AP14145 (10 mg·kg-1) did not trigger any apparent CNS effects in mice.CONCLUSIONS AND IMPLICATIONS: AP14145 is a negative allosteric modulator of KCa2.2 and KCa2.3 channels that shifted the calcium dependence of channel activation, an effect strongly dependent on two identified amino acids. AP14145 prolonged AERP in rats and did not trigger any acute CNS effects in mice. The understanding of how KCa2 channels are inhibited, at the molecular level, will help further development of drugs targeting KCa2 channels.

KW - Journal Article

U2 - 10.1111/bph.14043

DO - 10.1111/bph.14043

M3 - SCORING: Journal article

C2 - 28925012

VL - 174

SP - 4396

EP - 4408

JO - BRIT J PHARMACOL

JF - BRIT J PHARMACOL

SN - 0007-1188

IS - 23

ER -