ArticleMolecular pharmacology2014
Direct activation of β-cell KATP channels with a novel xanthine derivative.
Article in Molecular pharmacology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 49 citations in OpenAlex.
- Digenic HNF1A and ABCC8 variants provide mechanistic insight into early-onset diabetes.The Journal of clinical endocrinology and metabolism · 2026Article
- Automated patch clamp analysis of heterologously expressed Kir6.2/SUR1 and Kir6.1/SUR2B KAmerican journal of physiology. Cell physiology · 2025Article
- Characterization of four structurally diverse inhibitors of SUR2-containing KChannels (Austin, Tex.) · 2024Article
- Hypothalamic POMC neuron-specific knockout of MC4R affects insulin sensitivity by regulating Kir2.1.Molecular medicine (Cambridge, Mass.) · 2024Article
- Discovery and Characterization of VU0542270, the First Selective Inhibitor of Vascular Kir6.1/SUR2B KMolecular pharmacology · 2024Article
- Non-radioactive RbMethods in molecular biology (Clifton, N.J.) · 2024Article
- Pulmonary hypertension associated with diazoxide: the SUR1 paradox.ERJ open research · 2023Review
- Rapid Characterization of the Functional and Pharmacological Consequences of Cantú Syndrome KThe Journal of pharmacology and experimental therapeutics · 2023Article
- Synthesis and SAR of a novel Kir6.2/SUR1 channel opener scaffold identified by HTS.Bioorganic & medicinal chemistry letters · 2023Article
- Pharmacological Profiling of KPharmaceuticals (Basel, Switzerland) · 2023Article
- Personalized Therapeutics for KAnnual review of pharmacology and toxicology · 2023Review
- Targeting Host Sulphonyl Urea Receptor 2 Can Reduce Severity ofGastro hep advances · 2023Article
- VU6036720: The First Potent and Selective In Vitro Inhibitor of Heteromeric Kir4.1/5.1 Inward Rectifier Potassium Channels.Molecular pharmacology · 2022Article
- Lactate activation of α-cell KMolecular metabolism · 2020Article
- Tetraspanin-7 regulation of L-type voltage-dependent calcium channels controls pancreatic β-cell insulin secretion.The Journal of physiology · 2020Article
- Possible New Strategies for the Treatment of Congenital Hyperinsulinism.Frontiers in endocrinology · 2020Article
- The LRRC8 volume-regulated anion channel inhibitor, DCPIB, inhibits mitochondrial respiration independently of the channel.Physiological reports · 2019Article
- Structure-Activity Relationships, Pharmacokinetics, and Pharmacodynamics of the Kir6.2/SUR1-Specific Channel Opener VU0071063.The Journal of pharmacology and experimental therapeutics · 2019Article
- Pulmonary Hypertension and ATP-Sensitive Potassium Channels.Hypertension (Dallas, Tex. : 1979) · 2019Review
- Inward rectifier potassium (Kir) channels mediate salivary gland function and blood feeding in the lone star tick, Amblyomma americanum.PLoS neglected tropical diseases · 2019Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
ATP-regulated potassium (KATP) channel complexes of inward rectifier potassium channel (Kir) 6.2 and sulfonylurea receptor (SUR) 1 critically regulate pancreatic islet β-cell membrane potential, calcium influx, and insulin secretion, and consequently, represent important drug targets for metabolic disorders of glucose homeostasis. The KATP channel opener diazoxide is used clinically to treat intractable hypoglycemia caused by excessive insulin secretion, but its use is limited by off-target effects due to lack of potency and selectivity. Some progress has been made in developing improved Kir6.2/SUR1 agonists from existing chemical scaffolds and compound screening, but there are surprisingly few distinct chemotypes that are specific for SUR1-containing KATP channels. Here we report the serendipitous discovery in a high-throughput screen of a novel activator of Kir6.2/SUR1: VU0071063 [7-(4-(tert-butyl)benzyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione]. The xanthine derivative rapidly and dose-dependently activates Kir6.2/SUR1 with a half-effective concentration (EC50) of approximately 7 μM, is more efficacious than diazoxide at low micromolar concentrations, directly activates the channel in excised membrane patches, and is selective for SUR1- over SUR2A-containing Kir6.1 or Kir6.2 channels, as well as Kir2.1, Kir2.2, Kir2.3, Kir3.1/3.2, and voltage-gated potassium channel 2.1. Finally, we show that VU0071063 activates native Kir6.2/SUR1 channels, thereby inhibiting glucose-stimulated calcium entry in isolated mouse pancreatic β cells. VU0071063 represents a novel tool/compound for investigating β-cell physiology, KATP channel gating, and a new chemical scaffold for developing improved activators with medicinal chemistry.
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Registered trials
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.