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A New Negative Allosteric Modulator AP14145 for the Study of Small Conductance Calcium-Activated Potassium Channels

Publikation: Forskning - peer reviewTidsskriftartikel

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A New Negative Allosteric Modulator AP14145 for the Study of Small Conductance Calcium-Activated Potassium Channels. / Simo Vicens, Rafel; Kirchhoff, Jeppe Egedal; Dolce , Bernardo ; Abildgaard, Lea; Speerschneider, Tobias; Sørensen, Ulrik Svane; Grunnet, Morten; Diness, Jonas Goldin; Bentzen, Bo Hjorth.

I: British Journal of Pharmacology, 22.10.2017.

Publikation: Forskning - peer reviewTidsskriftartikel

Harvard

Simo 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 Channels' British Journal of Pharmacology. DOI: 10.1111/bph.14043

APA

Simo Vicens, R., Kirchhoff, J. E., Dolce , B., Abildgaard, L., Speerschneider, T., Sørensen, U. S., ... Bentzen, B. H. (2017). A New Negative Allosteric Modulator AP14145 for the Study of Small Conductance Calcium-Activated Potassium Channels. British Journal of Pharmacology. DOI: 10.1111/bph.14043

Vancouver

Simo Vicens R, Kirchhoff JE, Dolce B, Abildgaard L, Speerschneider T, Sørensen US o.a. A New Negative Allosteric Modulator AP14145 for the Study of Small Conductance Calcium-Activated Potassium Channels. British Journal of Pharmacology. 2017 okt 22. Tilgængelig fra, DOI: 10.1111/bph.14043

Author

Simo Vicens, Rafel ; Kirchhoff, Jeppe Egedal ; Dolce , Bernardo ; Abildgaard, Lea ; Speerschneider, Tobias ; Sørensen, Ulrik Svane ; Grunnet, Morten ; Diness, Jonas Goldin ; Bentzen, Bo Hjorth. / A New Negative Allosteric Modulator AP14145 for the Study of Small Conductance Calcium-Activated Potassium Channels. I: British Journal of Pharmacology. 2017

Bibtex

@article{e0f00d5ee69649ffa2e9a90d4e0786c9,
title = "A New Negative Allosteric Modulator AP14145 for the Study of Small Conductance Calcium-Activated Potassium Channels",
abstract = "Background and purpose: Small conductance Ca2+-activated K+ (KCa2) channels represent a promising atrial-selective target for treatment of atrial fibrillation (AF). Here, we establish the mechanism of KCa2 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 anaesthetised 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 L-1). The presence of AP14145 (10 μM L-1) increased the EC50 of Ca2+ on KCa2.3 from 0.36 ± 0.02 μM L-1 to 1.2 ± 0.1 μM L-1. The inhibitory effect strongly depended on two amino acids, S508 and A533. AP14145 concentration-dependently prolonged AERP in rats. Moreover, AP14145 (10 mg kg-1) did not trigger any apparent CNS effects in mice.Conclusion and implications: AP14145 is a negative allosteric modulator of KCa2.2 and KCa2.3 that shifts the calcium dependence of channel activation, an effect strongly dependent on two identified amino acids. AP14145 prolongs AERP in rats and does not trigger any acute CNS effects in mice. The understanding of how KCa2 inhibition is accomplished at the molecular level will help future development of drugs targeting KCa2 channels.",
keywords = "The Faculty of Health and Medical Sciences, AP14145, Atrial fibrillation, small conductance calcium-activated potassium channels, Electrophysiology, SK channel, negative allosteric modulator",
author = "{Simo Vicens}, Rafel and Kirchhoff, {Jeppe Egedal} and Bernardo Dolce and Lea Abildgaard and Tobias Speerschneider and Sørensen, {Ulrik Svane} and Morten Grunnet and Diness, {Jonas Goldin} and Bentzen, {Bo Hjorth}",
year = "2017",
month = "10",
doi = "10.1111/bph.14043",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "John/Wiley & Sons Ltd.",

}

RIS

TY - JOUR

T1 - A New Negative Allosteric Modulator AP14145 for the Study of Small Conductance Calcium-Activated Potassium Channels

AU - Simo Vicens,Rafel

AU - Kirchhoff,Jeppe Egedal

AU - Dolce ,Bernardo

AU - Abildgaard,Lea

AU - Speerschneider,Tobias

AU - Sørensen,Ulrik Svane

AU - Grunnet,Morten

AU - Diness,Jonas Goldin

AU - Bentzen,Bo Hjorth

PY - 2017/10/22

Y1 - 2017/10/22

N2 - Background and purpose: Small conductance Ca2+-activated K+ (KCa2) channels represent a promising atrial-selective target for treatment of atrial fibrillation (AF). Here, we establish the mechanism of KCa2 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 anaesthetised 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 L-1). The presence of AP14145 (10 μM L-1) increased the EC50 of Ca2+ on KCa2.3 from 0.36 ± 0.02 μM L-1 to 1.2 ± 0.1 μM L-1. The inhibitory effect strongly depended on two amino acids, S508 and A533. AP14145 concentration-dependently prolonged AERP in rats. Moreover, AP14145 (10 mg kg-1) did not trigger any apparent CNS effects in mice.Conclusion and implications: AP14145 is a negative allosteric modulator of KCa2.2 and KCa2.3 that shifts the calcium dependence of channel activation, an effect strongly dependent on two identified amino acids. AP14145 prolongs AERP in rats and does not trigger any acute CNS effects in mice. The understanding of how KCa2 inhibition is accomplished at the molecular level will help future development of drugs targeting KCa2 channels.

AB - Background and purpose: Small conductance Ca2+-activated K+ (KCa2) channels represent a promising atrial-selective target for treatment of atrial fibrillation (AF). Here, we establish the mechanism of KCa2 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 anaesthetised 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 L-1). The presence of AP14145 (10 μM L-1) increased the EC50 of Ca2+ on KCa2.3 from 0.36 ± 0.02 μM L-1 to 1.2 ± 0.1 μM L-1. The inhibitory effect strongly depended on two amino acids, S508 and A533. AP14145 concentration-dependently prolonged AERP in rats. Moreover, AP14145 (10 mg kg-1) did not trigger any apparent CNS effects in mice.Conclusion and implications: AP14145 is a negative allosteric modulator of KCa2.2 and KCa2.3 that shifts the calcium dependence of channel activation, an effect strongly dependent on two identified amino acids. AP14145 prolongs AERP in rats and does not trigger any acute CNS effects in mice. The understanding of how KCa2 inhibition is accomplished at the molecular level will help future development of drugs targeting KCa2 channels.

KW - The Faculty of Health and Medical Sciences

KW - AP14145

KW - Atrial fibrillation

KW - small conductance calcium-activated potassium channels

KW - Electrophysiology

KW - SK channel

KW - negative allosteric modulator

U2 - 10.1111/bph.14043

DO - 10.1111/bph.14043

M3 - Journal article

JO - British Journal of Pharmacology

T2 - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

ER -

ID: 183515098