ArticleACS chemical neuroscience2016
ML418: The First Selective, Sub-Micromolar Pore Blocker of Kir7.1 Potassium Channels.
Article in ACS chemical neuroscience, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 1 of them a synthesis that pooled it.
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Who cites it
22 citing papers in PubMed, 1 synthesis or guideline pooled it, 37 citations in OpenAlex.
- Potassium channels in intestinal epithelial cells and their pharmacological modulation: a systematic review.American journal of physiology. Cell physiology · 2021Pooled it
- Functional coupling between MC4R and Kir7.1 contributes to clozapine-induced weight gain in female mice.Nature communications · 2026Article
- Structural and functional studies of inward rectifier Kir7.1 and its regulation by the Melanocortin-4 receptor.Nature communications · 2026Article
- Bioactive lipid-mediated structural and functional regulation of the essential human potassium channel Kir7.1.Nature communications · 2026Article
- Contribution of glial inwardly rectifying potassium (Kir) channels to potassium buffering in insect neural systems.iScience · 2025Article
- Characterization of Next-Generation Inhibitors for the Inward-Rectifier Potassium Channel KACS medicinal chemistry letters · 2025Article
- Kir7.1 is the physiological target for hormones and steroids that regulate uteroplacental function.Science advances · 2025Article
- Characterization of four structurally diverse inhibitors of SUR2-containing KChannels (Austin, Tex.) · 2024Article
- Structure of the Ion Channel Kir7.1 and Implications for its Function in Normal and Pathophysiologic States.bioRxiv : the preprint server for biology · 2024Article
- Automated Patch Clamp Recordings of GPCR-Gated Ion Channels: Targeting the MC4-R/Kir7.1 Potassium Channel Complex.Methods in molecular biology (Clifton, N.J.) · 2024Article
- KAmerican journal of physiology. Renal physiology · 2023Article
- Synthesis of Bioactive Aminomethylated 8-Hydroxyquinolines via the Modified Mannich Reaction.International journal of molecular sciences · 2023Review
- Kir5.1 channels: potential role in epilepsy and seizure disorders.American journal of physiology. Cell physiology · 2022Review
- SUMOylation of Kir7.1 participates in neuropathic pain through regulating its membrane expression in spinal cord neurons.CNS neuroscience & therapeutics · 2022Article
- VU6036720: The First Potent and Selective In Vitro Inhibitor of Heteromeric Kir4.1/5.1 Inward Rectifier Potassium Channels.Molecular pharmacology · 2022Article
- Next-generation inward rectifier potassium channel modulators: discovery and molecular pharmacology.American journal of physiology. Cell physiology · 2021Review
- Therapeutic Antibodies Targeting Potassium Ion Channels.Handbook of experimental pharmacology · 2021Article
- Expression, localization, and functional properties of inwardly rectifying KAmerican journal of physiology. Renal physiology · 2020Review
- Synthesis and Cytoprotective Characterization of 8-Hydroxyquinoline Betti Products.Molecules (Basel, Switzerland) · 2018Article
- Discovery, Characterization, and Effects on Renal Fluid and Electrolyte Excretion of the Kir4.1 Potassium Channel Pore Blocker, VU0134992.Molecular pharmacology · 2018Article
Corrections and comments
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.