High-Throughput Screening Reveals a Small-Molecule Inhibitor of the Renal Outer Medullary Potassium Channel and Kir7.1

Abstract

The renal outer medullary potassium channel (ROMK) is ex-pressed 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 fluo-rescence-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 concentra-tions inhibit Kir7.1, making VU590 the first small-molecule in-hibitor of Kir7.1. Structure-activity relationships of VU590 wer