New positive Ca2+-activated K+ channel gating modulators with selectivity for KCa3.1

Nichole Coleman, Brandon M. Brown, Aida Oliván-Viguera, Vikrant Singh, Marilyn M. Olmstead, Marta Sofia Valero, Ralf Köhler, Heike Wulff

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Small-conductance (KCa2) and intermediate-conductance (K Ca3.1) calcium-activated K+ channels are voltage-independent and share a common calcium/calmodulin-mediated gating mechanism. Existing positive gating modulators like EBIO, NS309, or SKA-31 activate both KCa2 and KCa3.1 channels with similar potency or, as in the case of CyPPA and NS13001, selectively activate K Ca2.2 and KCa2.3 channels. We performed a structure-activity relationship (SAR) study with the aim of optimizing the benzothiazole pharmacophore of SKA-31 toward KCa3.1 selectivity. We identified SKA-111 (5-methylnaphtho[1,2-d]thiazol-2-amine), which displays 123-fold selectivity for KCa3.1 (EC50 111 ± 27 nM) over KCa2.3 (EC50 13.7 ± 6.9 μM), and SKA-121 (5-methylnaphtho [2,1-d]oxazol-2-amine), which displays 41-fold selectivity for KCa3.1 (EC50 109 nM ± 14 nM) over KCa2.3 (EC50 4.4 ± 1.6 μM). Both compounds are 200- to 400-fold selective over representative KV (KV1.3, KV2.1, KV3.1, and KV11.1), NaV (NaV1.2, NaV1.4, NaV 1.5, and NaV 1.7), as well as CaV1.2 channels. SKA-121 is a typical positive-gating modulator and shifts the calcium-concentration response curve of KCa3.1 to the left. In blood pressure telemetry experiments, SKA-121 (100 mg/kg i.p.) significantly lowered mean arterial blood pressure in normotensive and hypertensive wild-type but not in KCa3.1-/- mice. SKA-111, which was found in pharmacokinetic experiments to have a much longer half-life and to be much more brain penetrant than SKA-121, not only lowered blood pressure but also drastically reduced heart rate, presumably through cardiac and neuronal KCa2 activation when dosed at 100 mg/kg. In conclusion, with SKA-121, we generated a KCa3.1-specific positive gating modulator suitable for further exploring the therapeutical potential of KCa3.1 activation.

Original languageEnglish (US)
Pages (from-to)342-357
Number of pages16
JournalMolecular Pharmacology
Volume86
Issue number3
DOIs
StatePublished - 2014

Fingerprint

Calcium-Activated Potassium Channels
Arterial Pressure
Blood Pressure
Calcium
Telemetry
Calmodulin
Structure-Activity Relationship
Amines
Half-Life
5-methylnaphtho(2,1-d)oxazol-2-amine
Pharmacokinetics
Heart Rate
Brain

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Coleman, N., Brown, B. M., Oliván-Viguera, A., Singh, V., Olmstead, M. M., Valero, M. S., ... Wulff, H. (2014). New positive Ca2+-activated K+ channel gating modulators with selectivity for KCa3.1. Molecular Pharmacology, 86(3), 342-357. https://doi.org/10.1124/mol.114.093286

New positive Ca2+-activated K+ channel gating modulators with selectivity for KCa3.1. / Coleman, Nichole; Brown, Brandon M.; Oliván-Viguera, Aida; Singh, Vikrant; Olmstead, Marilyn M.; Valero, Marta Sofia; Köhler, Ralf; Wulff, Heike.

In: Molecular Pharmacology, Vol. 86, No. 3, 2014, p. 342-357.

Research output: Contribution to journalArticle

Coleman, N, Brown, BM, Oliván-Viguera, A, Singh, V, Olmstead, MM, Valero, MS, Köhler, R & Wulff, H 2014, 'New positive Ca2+-activated K+ channel gating modulators with selectivity for KCa3.1', Molecular Pharmacology, vol. 86, no. 3, pp. 342-357. https://doi.org/10.1124/mol.114.093286
Coleman N, Brown BM, Oliván-Viguera A, Singh V, Olmstead MM, Valero MS et al. New positive Ca2+-activated K+ channel gating modulators with selectivity for KCa3.1. Molecular Pharmacology. 2014;86(3):342-357. https://doi.org/10.1124/mol.114.093286
Coleman, Nichole ; Brown, Brandon M. ; Oliván-Viguera, Aida ; Singh, Vikrant ; Olmstead, Marilyn M. ; Valero, Marta Sofia ; Köhler, Ralf ; Wulff, Heike. / New positive Ca2+-activated K+ channel gating modulators with selectivity for KCa3.1. In: Molecular Pharmacology. 2014 ; Vol. 86, No. 3. pp. 342-357.
@article{671d6103b5084991b35333852450cedc,
title = "New positive Ca2+-activated K+ channel gating modulators with selectivity for KCa3.1",
abstract = "Small-conductance (KCa2) and intermediate-conductance (K Ca3.1) calcium-activated K+ channels are voltage-independent and share a common calcium/calmodulin-mediated gating mechanism. Existing positive gating modulators like EBIO, NS309, or SKA-31 activate both KCa2 and KCa3.1 channels with similar potency or, as in the case of CyPPA and NS13001, selectively activate K Ca2.2 and KCa2.3 channels. We performed a structure-activity relationship (SAR) study with the aim of optimizing the benzothiazole pharmacophore of SKA-31 toward KCa3.1 selectivity. We identified SKA-111 (5-methylnaphtho[1,2-d]thiazol-2-amine), which displays 123-fold selectivity for KCa3.1 (EC50 111 ± 27 nM) over KCa2.3 (EC50 13.7 ± 6.9 μM), and SKA-121 (5-methylnaphtho [2,1-d]oxazol-2-amine), which displays 41-fold selectivity for KCa3.1 (EC50 109 nM ± 14 nM) over KCa2.3 (EC50 4.4 ± 1.6 μM). Both compounds are 200- to 400-fold selective over representative KV (KV1.3, KV2.1, KV3.1, and KV11.1), NaV (NaV1.2, NaV1.4, NaV 1.5, and NaV 1.7), as well as CaV1.2 channels. SKA-121 is a typical positive-gating modulator and shifts the calcium-concentration response curve of KCa3.1 to the left. In blood pressure telemetry experiments, SKA-121 (100 mg/kg i.p.) significantly lowered mean arterial blood pressure in normotensive and hypertensive wild-type but not in KCa3.1-/- mice. SKA-111, which was found in pharmacokinetic experiments to have a much longer half-life and to be much more brain penetrant than SKA-121, not only lowered blood pressure but also drastically reduced heart rate, presumably through cardiac and neuronal KCa2 activation when dosed at 100 mg/kg. In conclusion, with SKA-121, we generated a KCa3.1-specific positive gating modulator suitable for further exploring the therapeutical potential of KCa3.1 activation.",
author = "Nichole Coleman and Brown, {Brandon M.} and Aida Oliv{\'a}n-Viguera and Vikrant Singh and Olmstead, {Marilyn M.} and Valero, {Marta Sofia} and Ralf K{\"o}hler and Heike Wulff",
year = "2014",
doi = "10.1124/mol.114.093286",
language = "English (US)",
volume = "86",
pages = "342--357",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

TY - JOUR

T1 - New positive Ca2+-activated K+ channel gating modulators with selectivity for KCa3.1

AU - Coleman, Nichole

AU - Brown, Brandon M.

AU - Oliván-Viguera, Aida

AU - Singh, Vikrant

AU - Olmstead, Marilyn M.

AU - Valero, Marta Sofia

AU - Köhler, Ralf

AU - Wulff, Heike

PY - 2014

Y1 - 2014

N2 - Small-conductance (KCa2) and intermediate-conductance (K Ca3.1) calcium-activated K+ channels are voltage-independent and share a common calcium/calmodulin-mediated gating mechanism. Existing positive gating modulators like EBIO, NS309, or SKA-31 activate both KCa2 and KCa3.1 channels with similar potency or, as in the case of CyPPA and NS13001, selectively activate K Ca2.2 and KCa2.3 channels. We performed a structure-activity relationship (SAR) study with the aim of optimizing the benzothiazole pharmacophore of SKA-31 toward KCa3.1 selectivity. We identified SKA-111 (5-methylnaphtho[1,2-d]thiazol-2-amine), which displays 123-fold selectivity for KCa3.1 (EC50 111 ± 27 nM) over KCa2.3 (EC50 13.7 ± 6.9 μM), and SKA-121 (5-methylnaphtho [2,1-d]oxazol-2-amine), which displays 41-fold selectivity for KCa3.1 (EC50 109 nM ± 14 nM) over KCa2.3 (EC50 4.4 ± 1.6 μM). Both compounds are 200- to 400-fold selective over representative KV (KV1.3, KV2.1, KV3.1, and KV11.1), NaV (NaV1.2, NaV1.4, NaV 1.5, and NaV 1.7), as well as CaV1.2 channels. SKA-121 is a typical positive-gating modulator and shifts the calcium-concentration response curve of KCa3.1 to the left. In blood pressure telemetry experiments, SKA-121 (100 mg/kg i.p.) significantly lowered mean arterial blood pressure in normotensive and hypertensive wild-type but not in KCa3.1-/- mice. SKA-111, which was found in pharmacokinetic experiments to have a much longer half-life and to be much more brain penetrant than SKA-121, not only lowered blood pressure but also drastically reduced heart rate, presumably through cardiac and neuronal KCa2 activation when dosed at 100 mg/kg. In conclusion, with SKA-121, we generated a KCa3.1-specific positive gating modulator suitable for further exploring the therapeutical potential of KCa3.1 activation.

AB - Small-conductance (KCa2) and intermediate-conductance (K Ca3.1) calcium-activated K+ channels are voltage-independent and share a common calcium/calmodulin-mediated gating mechanism. Existing positive gating modulators like EBIO, NS309, or SKA-31 activate both KCa2 and KCa3.1 channels with similar potency or, as in the case of CyPPA and NS13001, selectively activate K Ca2.2 and KCa2.3 channels. We performed a structure-activity relationship (SAR) study with the aim of optimizing the benzothiazole pharmacophore of SKA-31 toward KCa3.1 selectivity. We identified SKA-111 (5-methylnaphtho[1,2-d]thiazol-2-amine), which displays 123-fold selectivity for KCa3.1 (EC50 111 ± 27 nM) over KCa2.3 (EC50 13.7 ± 6.9 μM), and SKA-121 (5-methylnaphtho [2,1-d]oxazol-2-amine), which displays 41-fold selectivity for KCa3.1 (EC50 109 nM ± 14 nM) over KCa2.3 (EC50 4.4 ± 1.6 μM). Both compounds are 200- to 400-fold selective over representative KV (KV1.3, KV2.1, KV3.1, and KV11.1), NaV (NaV1.2, NaV1.4, NaV 1.5, and NaV 1.7), as well as CaV1.2 channels. SKA-121 is a typical positive-gating modulator and shifts the calcium-concentration response curve of KCa3.1 to the left. In blood pressure telemetry experiments, SKA-121 (100 mg/kg i.p.) significantly lowered mean arterial blood pressure in normotensive and hypertensive wild-type but not in KCa3.1-/- mice. SKA-111, which was found in pharmacokinetic experiments to have a much longer half-life and to be much more brain penetrant than SKA-121, not only lowered blood pressure but also drastically reduced heart rate, presumably through cardiac and neuronal KCa2 activation when dosed at 100 mg/kg. In conclusion, with SKA-121, we generated a KCa3.1-specific positive gating modulator suitable for further exploring the therapeutical potential of KCa3.1 activation.

UR - http://www.scopus.com/inward/record.url?scp=84906308946&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84906308946&partnerID=8YFLogxK

U2 - 10.1124/mol.114.093286

DO - 10.1124/mol.114.093286

M3 - Article

C2 - 24958817

AN - SCOPUS:84906308946

VL - 86

SP - 342

EP - 357

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 3

ER -