Characterization of the pharmacology of YM-198313 on volume-regulated anion channels.
Activation of the volume-regulated anion channels (VRAC) is considered to be involved in arrhythmia, but it has not yet been fully elucidated because of the lack of its high affinitive and selective compounds. A newly synthesized compound, YM-198313 (sodium 4-({[2-(methylthio)benzyl]amino}-5-[(1-phenylethyl)thio]isothiazol-3-olate), strongly inhibited VRAC in HeLa cells with an IC50 of 3.03+/-0.05 microM. However, YM-198313 weakly affected both the Ca2+-activated Cl- channels in HTC cells and the cAMP-activated Cl- channels in T84 cells, demonstrating that this compound is selective for VRAC among Cl- channels. At 10 microM, YM-198313 almost completely (100+/-7.8%) inhibited the VRAC current in guinea pig atrial myocytes. However, at the same concentration, YM-198313 showed little inhibitory effect on the cardiac cation currents in ventricular myocytes. We believe that YM-198313 is a potent and selective VRAC inhibitor, therefore, it should be use to clarify the role VRAC plays in arrhythmia.
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan. hiroshi-shibata@jp.astellas.com
Hiroshi
H
Shibata
Tomo-Oki
TO
Satoh
Tohru
T
Ugawa
Noriyuki
N
Masuda
Hiroko
H
Yanai-Inamura
Asaki
A
Abe
Yasuhiro
Y
Kondo
Takahiro
T
Kuramochi
Seijiro
S
Akamatsu
Wataru
W
Uchida
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001593:Benzyl Compounds / Q000494:pharmacology*; D065101:Chloride Channel Agonists; D018118:Chloride Channels / Q000502:physiology; D006168:Guinea Pigs; D006367:HeLa Cells; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D009994:Osmolar Concentration; D013844:Thiazoles / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D001593:Benzyl Compounds; D065101:Chloride Channel Agonists; D018118:Chloride Channels; D013844:Thiazoles; C504646:sodium 4-((2-(methylthio)benzyl)amino)-5-((1-phenylethyl)thio)isothiazol-3-olate