Gautam Bhave
Faculty Member
Last active: 8/12/2015

High-throughput screening reveals a small-molecule inhibitor of the renal outer medullary potassium channel and Kir7.1.

Lewis LM, Bhave G, Chauder BA, Banerjee S, Lornsen KA, Redha R, Fallen K, Lindsley CW, Weaver CD, Denton JS
Mol Pharmacol. 2009 76 (5): 1094-103

PMID: 19706730 · PMCID: PMC2774996 · DOI:10.1124/mol.109.059840

The renal outer medullary potassium channel (ROMK) is expressed in the kidney tubule and critically regulates sodium and potassium balance. The physiological functions of other inward rectifying K(+) (Kir) channels expressed in the nephron, such as Kir7.1, are less well understood in part due to the lack of selective pharmacological probes targeting inward rectifiers. In an effort to identify Kir channel probes, we performed a fluorescence-based, high-throughput screen (HTS) of 126,009 small molecules for modulators of ROMK function. Several antagonists were identified in the screen. One compound, termed VU590, inhibits ROMK with submicromolar affinity, but has no effect on Kir2.1 or Kir4.1. Low micromolar concentrations inhibit Kir7.1, making VU590 the first small-molecule inhibitor of Kir7.1. Structure-activity relationships of VU590 were defined using small-scale parallel synthesis. Electrophysiological analysis indicates that VU590 is an intracellular pore blocker. VU590 and other compounds identified by HTS will be instrumental in defining Kir channel structure, physiology, and therapeutic potential.

MeSH Terms (10)

Animals Cell Line Genetic Testing Heterocyclic Compounds, 1-Ring Humans Kidney Medulla Potassium Channel Blockers Potassium Channels, Inwardly Rectifying Rats Small Molecule Libraries

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