ML418: The First Selective, Sub-Micromolar Pore Blocker of Kir7.1 Potassium Channels

Daniel R. Swale, Haruto Kurata, Sujay V. Kharade, Jonathan Sheehan, Rene Raphemot, Karl R. Voigtritter, Eric E. Figueroa, Jens Meiler, Anna L. Blobaum, Craig W. Lindsley, Corey R. Hopkins, Jerod S. Denton

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The inward rectifier potassium (Kir) channel Kir7.1 (KCNJ13) has recently emerged as a key regulator of melanocortin signaling in the brain, electrolyte homeostasis in the eye, and uterine muscle contractility during pregnancy. The pharmacological tools available for exploring the physiology and therapeutic potential of Kir7.1 have been limited to relatively weak and nonselective small-molecule inhibitors. Here, we report the discovery in a fluorescence-based high-throughput screen of a novel Kir7.1 channel inhibitor, VU714. Site-directed mutagenesis of pore-lining amino acid residues identified glutamate 149 and alanine 150 as essential determinants of VU714 activity. Lead optimization with medicinal chemistry generated ML418, which exhibits sub-micromolar activity (IC50 = 310 nM) and superior selectivity over other Kir channels (at least 17-fold selective over Kir1.1, Kir2.1, Kir2.2, Kir2.3, Kir3.1/3.2, and Kir4.1) except for Kir6.2/SUR1 (equally potent). Evaluation in the EuroFins Lead Profiling panel of 64 GPCRs, ion-channels, and transporters for off-target activity of ML418 revealed a relatively clean ancillary pharmacology. While ML418 exhibited low CLHEP in human microsomes which could be modulated with lipophilicity adjustments, it showed high CLHEP in rat microsomes regardless of lipophilicity. A subsequent in vivo PK study of ML418 by intraperitoneal (IP) administration (30 mg/kg dosage) revealed a suitable PK profile (Cmax = 0.20 μM and Tmax = 3 h) and favorable CNS distribution (mouse brain/plasma Kp of 10.9 to support in vivo studies. ML418, which represents the current state-of-the-art in Kir7.1 inhibitors, should be useful for exploring the physiology of Kir7.1 in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)1013-1023
Number of pages11
JournalACS Chemical Neuroscience
Volume7
Issue number7
DOIs
StatePublished - Jul 20 2016

Fingerprint

Potassium Channels
Physiology
Microsomes
Brain
Potassium
Pharmacology
Melanocortins
Inwardly Rectifying Potassium Channel
Mutagenesis
Pharmaceutical Chemistry
Myometrium
Site-Directed Mutagenesis
Ion Channels
Linings
Alanine
Electrolytes
Inhibitory Concentration 50
Muscle
Rats
Glutamic Acid

Keywords

  • KCNJ13
  • comparative modeling
  • electrophysiology
  • melanocortin signaling
  • myometrium
  • thallium flux

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

Cite this

Swale, D. R., Kurata, H., Kharade, S. V., Sheehan, J., Raphemot, R., Voigtritter, K. R., ... Denton, J. S. (2016). ML418: The First Selective, Sub-Micromolar Pore Blocker of Kir7.1 Potassium Channels. ACS Chemical Neuroscience, 7(7), 1013-1023. https://doi.org/10.1021/acschemneuro.6b00111

ML418 : The First Selective, Sub-Micromolar Pore Blocker of Kir7.1 Potassium Channels. / Swale, Daniel R.; Kurata, Haruto; Kharade, Sujay V.; Sheehan, Jonathan; Raphemot, Rene; Voigtritter, Karl R.; Figueroa, Eric E.; Meiler, Jens; Blobaum, Anna L.; Lindsley, Craig W.; Hopkins, Corey R.; Denton, Jerod S.

In: ACS Chemical Neuroscience, Vol. 7, No. 7, 20.07.2016, p. 1013-1023.

Research output: Contribution to journalArticle

Swale, DR, Kurata, H, Kharade, SV, Sheehan, J, Raphemot, R, Voigtritter, KR, Figueroa, EE, Meiler, J, Blobaum, AL, Lindsley, CW, Hopkins, CR & Denton, JS 2016, 'ML418: The First Selective, Sub-Micromolar Pore Blocker of Kir7.1 Potassium Channels', ACS Chemical Neuroscience, vol. 7, no. 7, pp. 1013-1023. https://doi.org/10.1021/acschemneuro.6b00111
Swale DR, Kurata H, Kharade SV, Sheehan J, Raphemot R, Voigtritter KR et al. ML418: The First Selective, Sub-Micromolar Pore Blocker of Kir7.1 Potassium Channels. ACS Chemical Neuroscience. 2016 Jul 20;7(7):1013-1023. https://doi.org/10.1021/acschemneuro.6b00111
Swale, Daniel R. ; Kurata, Haruto ; Kharade, Sujay V. ; Sheehan, Jonathan ; Raphemot, Rene ; Voigtritter, Karl R. ; Figueroa, Eric E. ; Meiler, Jens ; Blobaum, Anna L. ; Lindsley, Craig W. ; Hopkins, Corey R. ; Denton, Jerod S. / ML418 : The First Selective, Sub-Micromolar Pore Blocker of Kir7.1 Potassium Channels. In: ACS Chemical Neuroscience. 2016 ; Vol. 7, No. 7. pp. 1013-1023.
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