title: Direct activation of β-cell KATP channels with a novel xanthine derivative.
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.
authors.affiliation: Departments of Anesthesiology (R.R., D.R.S., S.B., J.S.D.), Pharmacology (R.R., J.S.D.), and Molecular Physiology and Biophysics (P.K.D., D.A.J.) and Institutes of Chemical Biology (J.S.D.) and Global Health (J.S.D.), Vanderbilt University Medical Center, Nashville, Tennessee; Department of Medicine, University of Rochester Medical Center, Rochester, New York (A.P.W.); and Department of Cell Biology and Physiology (P.C., C.G.N.) and Center for the Investigation of Membrane Excitability Disorders (P.C., C.G.N.), Washington University School of Medicine in St. Louis, St. Louis, Missouri.
authors.forename: Rene
authors.initials: R
authors.lastname: Raphemot
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Swale
authors.forename: Prasanna K
authors.initials: PK
authors.lastname: Dadi
authors.forename: David A
authors.initials: DA
authors.lastname: Jacobson
authors.forename: Paige
authors.initials: P
authors.lastname: Cooper
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Wojtovich
authors.forename: Sreedatta
authors.initials: S
authors.lastname: Banerjee
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
authors.forename: Jerod S
authors.initials: JS
authors.lastname: Denton
mesh_terms: D005947:Glucose / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D054086:KATP Channels / Q000819:agonists*; D018408:Patch-Clamp Techniques; D013329:Structure-Activity Relationship; D064233:Sulfonylurea Receptors / Q000819:agonists; D019820:Xanthine / Q000494:pharmacology*; D014970:Xanthines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000589028:7-(4-(tert-butyl)benzyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione; D054086:KATP Channels; D064233:Sulfonylurea Receptors; D014970:Xanthines; D019820:Xanthine; D005947:Glucose