Format

Send to

Choose Destination
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.

Author information

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

Abstract

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.

KEYWORDS:

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

PMID:
23838260
PMCID:
PMC3816575
DOI:
10.1016/j.bmcl.2013.06.023
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center