RT Journal Article
SR Electronic
T1 High-Throughput Screening Reveals a Small-Molecule Inhibitor of the Renal Outer Medullary Potassium Channel and Kir7.1
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1094
OP 1103
DO 10.1124/mol.109.059840
VO 76
IS 5
A1 Lewis, L. Michelle
A1 Bhave, Gautam
A1 Chauder, Brian A.
A1 Banerjee, Sreedatta
A1 Lornsen, Katharina A.
A1 Redha, Rey
A1 Fallen, Katherine
A1 Lindsley, Craig W.
A1 Weaver, C. David
A1 Denton, Jerod S.
YR 2009
UL http://molpharm.aspetjournals.org/content/76/5/1094.abstract
AB 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. © 2009 The American Society for Pharmacology and Experimental Therapeutics