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Research ArticleArticle

Identification and Characterization of a Novel Large-Conductance Calcium-Activated Potassium Channel Activator, CTIBD, and Its Relaxation Effect on Urinary Bladder Smooth Muscle

Narasaem Lee, Bong Hee Lim, Kyu-Sung Lee, Jimin Shin, Haushabhau S. Pagire, Suvarna H. Pagire, Jin Hee Ahn, Sung Won Lee, Tong Mook Kang and Chul-Seung Park
Molecular Pharmacology February 2021, 99 (2) 114-124; DOI: https://doi.org/10.1124/molpharm.120.000106
Narasaem Lee
School of Life Sciences, Center for AI-applied High Efficiency Drug Discovery and Integrated Institute of Biomedical Research (N.L., C.-S.P.) and Department of Chemistry (H.S.P., S.H.P., J.H.A.), Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea; Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea (B.H.L., K.-S.L., J.S., S.W.L.); and Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, South Korea (T.M.K.)
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Bong Hee Lim
School of Life Sciences, Center for AI-applied High Efficiency Drug Discovery and Integrated Institute of Biomedical Research (N.L., C.-S.P.) and Department of Chemistry (H.S.P., S.H.P., J.H.A.), Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea; Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea (B.H.L., K.-S.L., J.S., S.W.L.); and Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, South Korea (T.M.K.)
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Kyu-Sung Lee
School of Life Sciences, Center for AI-applied High Efficiency Drug Discovery and Integrated Institute of Biomedical Research (N.L., C.-S.P.) and Department of Chemistry (H.S.P., S.H.P., J.H.A.), Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea; Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea (B.H.L., K.-S.L., J.S., S.W.L.); and Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, South Korea (T.M.K.)
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Jimin Shin
School of Life Sciences, Center for AI-applied High Efficiency Drug Discovery and Integrated Institute of Biomedical Research (N.L., C.-S.P.) and Department of Chemistry (H.S.P., S.H.P., J.H.A.), Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea; Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea (B.H.L., K.-S.L., J.S., S.W.L.); and Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, South Korea (T.M.K.)
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Haushabhau S. Pagire
School of Life Sciences, Center for AI-applied High Efficiency Drug Discovery and Integrated Institute of Biomedical Research (N.L., C.-S.P.) and Department of Chemistry (H.S.P., S.H.P., J.H.A.), Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea; Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea (B.H.L., K.-S.L., J.S., S.W.L.); and Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, South Korea (T.M.K.)
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Suvarna H. Pagire
School of Life Sciences, Center for AI-applied High Efficiency Drug Discovery and Integrated Institute of Biomedical Research (N.L., C.-S.P.) and Department of Chemistry (H.S.P., S.H.P., J.H.A.), Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea; Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea (B.H.L., K.-S.L., J.S., S.W.L.); and Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, South Korea (T.M.K.)
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Jin Hee Ahn
School of Life Sciences, Center for AI-applied High Efficiency Drug Discovery and Integrated Institute of Biomedical Research (N.L., C.-S.P.) and Department of Chemistry (H.S.P., S.H.P., J.H.A.), Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea; Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea (B.H.L., K.-S.L., J.S., S.W.L.); and Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, South Korea (T.M.K.)
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Sung Won Lee
School of Life Sciences, Center for AI-applied High Efficiency Drug Discovery and Integrated Institute of Biomedical Research (N.L., C.-S.P.) and Department of Chemistry (H.S.P., S.H.P., J.H.A.), Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea; Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea (B.H.L., K.-S.L., J.S., S.W.L.); and Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, South Korea (T.M.K.)
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Tong Mook Kang
School of Life Sciences, Center for AI-applied High Efficiency Drug Discovery and Integrated Institute of Biomedical Research (N.L., C.-S.P.) and Department of Chemistry (H.S.P., S.H.P., J.H.A.), Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea; Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea (B.H.L., K.-S.L., J.S., S.W.L.); and Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, South Korea (T.M.K.)
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Chul-Seung Park
School of Life Sciences, Center for AI-applied High Efficiency Drug Discovery and Integrated Institute of Biomedical Research (N.L., C.-S.P.) and Department of Chemistry (H.S.P., S.H.P., J.H.A.), Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea; Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea (B.H.L., K.-S.L., J.S., S.W.L.); and Department of Physiology, Sungkyunkwan University School of Medicine, Suwon, South Korea (T.M.K.)
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Abstract

The large-conductance calcium-activated potassium channel (BKCa channel) is expressed on various tissues and is involved in smooth muscle relaxation. The channel is highly expressed on urinary bladder smooth muscle cells and regulates the repolarization phase of the spontaneous action potentials that control muscle contraction. To discover novel chemical activators of the BKCa channel, we screened a chemical library containing 8364 chemical compounds using a cell-based fluorescence assay. A chemical compound containing an isoxazolyl benzene skeleton (compound 1) was identified as a potent activator of the BKCa channel and was structurally optimized through a structure-activity relationship study to obtain 4-(4-(4-chlorophenyl)-3-(trifluoromethyl)isoxazol-5-yl)benzene-1,3-diol (CTIBD). When CTIBD was applied to the treated extracellular side of the channel, the conductance-voltage relationship of the channel shifted toward a negative value, and the maximum conductance increased in a concentration-dependent manner. CTIBD altered the gating kinetics of the channel by dramatically slowing channel closing without effecting channel opening. The effects of CTIBD on bladder muscle relaxation and micturition function were tested in rat tissue and in vivo. CTIBD concentration-dependently reduced acetylcholine-induced contraction of urinary bladder smooth muscle strips. In an acetic acid–induced overactive bladder (OAB) model, intraperitoneal injection of 20 mg/kg CTIBD effectively restored frequent voiding contraction and lowered voiding volume without affecting other bladder function parameters. Thus, our results indicate that CTIBD and its derivatives are novel chemical activators of the bladder BKCa channel and potential candidates for OAB therapeutics.

SIGNIFICANCE STATEMENT The novel BKCa channel activator CTIBD was identified and characterized in this study. CTIBD directly activates the BKCa channel and relaxes urinary bladder smooth muscle of rat, so CTIBD can be a potential candidate for overactive bladder therapeutics.

Footnotes

    • Received June 30, 2020.
    • Accepted November 11, 2020.
  • This work was supported by the Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, and Forestry (IPET) through the Agri-Bio Industry Technology Development Program; funded by the Ministry of Agriculture, Food and Rural Affairs (MAFRA) [317070-4]; and supported by a Gwangju Institute of Science and Technology (GIST) Research Institute (GRI) Integrated Institute of Biomedical Research (IIBR) grant funded in 2020.

  • https://doi.org/10.1124/molpharm.120.000106.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 99 (2)
Molecular Pharmacology
Vol. 99, Issue 2
1 Feb 2021
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Research ArticleArticle

Bladder Relaxation Effect of BKCa Channel Activator CTIBD

Narasaem Lee, Bong Hee Lim, Kyu-Sung Lee, Jimin Shin, Haushabhau S. Pagire, Suvarna H. Pagire, Jin Hee Ahn, Sung Won Lee, Tong Mook Kang and Chul-Seung Park
Molecular Pharmacology February 1, 2021, 99 (2) 114-124; DOI: https://doi.org/10.1124/molpharm.120.000106

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Research ArticleArticle

Bladder Relaxation Effect of BKCa Channel Activator CTIBD

Narasaem Lee, Bong Hee Lim, Kyu-Sung Lee, Jimin Shin, Haushabhau S. Pagire, Suvarna H. Pagire, Jin Hee Ahn, Sung Won Lee, Tong Mook Kang and Chul-Seung Park
Molecular Pharmacology February 1, 2021, 99 (2) 114-124; DOI: https://doi.org/10.1124/molpharm.120.000106
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