title: 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 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.
authors.affiliation: Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: L Michelle
authors.initials: LM
authors.lastname: Lewis
authors.forename: Gautam
authors.initials: G
authors.lastname: Bhave
authors.forename: Brian A
authors.initials: BA
authors.lastname: Chauder
authors.forename: Sreedatta
authors.initials: S
authors.lastname: Banerjee
authors.forename: Katharina A
authors.initials: KA
authors.lastname: Lornsen
authors.forename: Rey
authors.initials: R
authors.lastname: Redha
authors.forename: Katherine
authors.initials: K
authors.lastname: Fallen
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
authors.forename: Jerod S
authors.initials: JS
authors.lastname: Denton
mesh_terms: D000818:Animals; D002460:Cell Line; D005820:Genetic Testing / Q000379:methods*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007679:Kidney Medulla / Q000187:drug effects / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000502:physiology*; D051381:Rats; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C544855:7,13-bis(4-nitrobenzyl)-1,4,10-trioxa-7,13-diazacyclopentadecane; D006573:Heterocyclic Compounds, 1-Ring; C489477:Kir7.1 channel; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D054852:Small Molecule Libraries
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