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Discovery of an inward rectifying potassium channel inhibitor with preference for Kir2.3 and Kir3
Author(s) -
Raphemot Rene,
Lonergan Daniel,
Nguyen Thuy T.,
Utley Thomas J.,
Gogliotti Rocco,
Hopkins Corey R.,
Lewis L. Michelle,
Lindsley Craig W.,
Weaver C. David,
Denton Jerod S.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1098.3
Subject(s) - homomeric , inward rectifier potassium ion channel , potassium channel , chemistry , pharmacology , ion channel , repolarization , drug action , drug , drug discovery , electrophysiology , potassium channel blocker , potency , cardiac action potential , membrane potential , in vitro , biophysics , biology , biochemistry , receptor , neuroscience , protein subunit , gene
Inward rectifying potassium (Kir) channels play key physiological roles in diverse cell types and may represent novel drug targets for disease. In cardiac myocytes, Kir channels contribute to the resting membrane potential and the late repolarization phase of the action potential. Homomeric Kir2.3 and heteromeric Kir3.1/3.4 channels are expressed almost exclusively in the atria and are postulated drug targets for atrial fibrillation, a common arrhythmia that predisposes patients to stroke. Efforts to assess the utility of Kir2.3 and Kir3.1/3.4 channels as therapeutic targets have been hampered by the lack of drug‐like compounds targeting these channels. We therefore performed a fluorescence‐based high‐throughput screen for small‐molecule inhibitors of Kir3.X channel function. Several novel inhibitors were discovered. One compound, termed VU573, inhibits Kir3.X channels with a half‐maximal inhibition concentration of 1.6 μM. Subsequent electrophysiology‐based counterscreens revealed that VU573 inhibits Kir2.3 with equal potency, but is less active toward Kir1.1, Kir2.1, Kir4.1 and Kir7.1. We are currently using medicinal chemistry to improve the potency and selectivity of VU573 for Kir2.3 and Kir3.X and understand the structural requirements for inhibition of these channels.