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.
Footnotes
- Received January 20, 2014.
- Accepted March 19, 2014.
This work was supported by the Foundation for the National Institutes of Health Vector-Based Transmission Control program of the Grand Challenges in Global Health initiative [Grant PIER11VCTR]; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants 1R01-DK082884 and 5R03-DK096122]; the National Institutes of Health National Heart, Lung, and Blood Institute [Grant R01-HL95010]; and the American Heart Association, Founder’s Affiliate Postdoctoral Fellowship [Grant 11POST7290028]. A.P.W. acknowledges support from Paul S. Brookes and Keith Nehrke (University of Rochester); work in whose laboratories is funded by the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM087483].
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- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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