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

Autor:	Lee N; 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.)., Lim BH; 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.)., Lee KS; 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.)., Shin J; 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.)., Pagire HS; 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.)., Pagire SH; 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.)., Ahn JH; 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.)., Lee SW; 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.)., Kang TM; 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.)., Park CS; 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.) cspark@gist.ac.kr.
Jazyk:	angličtina
Zdroj:	Molecular pharmacology [Mol Pharmacol] 2021 Feb; Vol. 99 (2), pp. 114-124. Date of Electronic Publication: 2020 Dec 02.
DOI:	10.1124/molpharm.120.000106
Abstrakt:	The large-conductance calcium-activated potassium channel (BK Ca 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 BK Ca 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 BK Ca 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 BK Ca channel and potential candidates for OAB therapeutics. SIGNIFICANCE STATEMENT: The novel BK Ca channel activator CTIBD was identified and characterized in this study. CTIBD directly activates the BK Ca channel and relaxes urinary bladder smooth muscle of rat, so CTIBD can be a potential candidate for overactive bladder therapeutics. (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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