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Bioorg Med Chem Lett. 2013 Aug 15;23(16):4562-6. doi: 10.1016/j.bmcl.2013.06.023. Epub 2013 Jun 20.

Discovery of 'molecular switches' within a GIRK activator scaffold that afford selective GIRK inhibitors.

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  • 1College of Science, Northwest Agriculture & Forestry University, Yangling, Shaanxi 712100, China.


This letter describes a multi-dimensional SAR campaign based on a potent, efficacious and selective GIRK1/2 activator (~10-fold versus GIRK1/4 and inactive on nonGIRK 1-containing GIRKs, GIRK 2 or GIRK2/3). Further chemical optimization through an iterative parallel synthesis effort identified multiple 'molecular switches' that modulated the mode of pharmacology from activator to inhibitor, as well as engendering varying selectivity profiles for GIRK1/2 and GIRK1/4. Importantly, these compounds were all inactive on nonGIRK1 containing GIRK channels. However, SAR was challenging as subtle structural modifications had large effects on both mode of pharmacology and GIRK1/2 and GIRK1/4 channel selectivity.

Copyright © 2013 Elsevier Ltd. All rights reserved.


Activators; GIRK; Inhibitors; K(ir)3.x; Thallium flux

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