Research Papers: Gerotarget (Focus on Aging):
Novel inhibitor candidates of TRPV2 prevent damage of dystrophic myocytes and ameliorate against dilated cardiomyopathy in a hamster model
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Yuko Iwata1, Yoshimi Katayama2,5, Yasushi Okuno3 and Shigeo Wakabayashi4,6
1Departments of Molecular Physiology and Clinical Research, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan
2Pharmacological Research Laboratories, Drug Safety Testing Center Co., Ltd., Higashimatsuyama, Saitama, Japan
3Department of Clinical System Onco-Informatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
4Departments of Molecular Physiology and Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan
5Present affiliation: Biological Research Laboratories, Nissan Chemical Industries, Ltd, Shiraoka, Saitama, Japan
6Present affiliation: Department of Pharmocology, Osaka Medical Collage, Takatsuki, Osaka, Japan
Yuko Iwata, email: email@example.com
Keywords: cardiomyopathy; muscular dystrophy; Ca2+ influx; Ca2+-permeable channel; therapy; Gerotarget
Received: January 26, 2018 Accepted: February 01, 2018 Epub: February 08, 2018 Published: March 06, 2018
Transient receptor potential cation channel, subfamily V, member 2 (TRPV2) is a principal candidate for abnormal Ca2+-entry pathways, which is a potential target for therapy of muscular dystrophy and cardiomyopathy. Here, an in silico drug screening and the following cell-based screening to measure the TRPV2 activation were carried out in HEK293 cells expressing TRPV2 using lead compounds (tranilast or SKF96365) and off-patent drug stocks. We identified 4 chemical compounds containing amino-benzoyl groups and 1 compound (lumin) containing an ethylquinolinium group as candidate TRPV2 inhibitors. Three of these compounds inhibited Ca2+ entry through both mouse and human TRPV2, with IC50 of less than 10 μM, but had no apparent effect on other members of TRP family such as TRPV1 and TRPC1. Particularly, lumin inhibited agonist-induced TRPV2 channel activity at a low dose. These compounds inhibited abnormally increased Ca2+ influx and prevented stretch-induced skeletal muscle damage in cultured myocytes from dystrophic hamsters (J2N-k). Further, they ameliorated cardiac dysfunction, and prevented disease progression in vivo in the same J2N-k hamsters developing dilated cardiomyopathy as well as muscular dystrophy. The identified compounds described here are available as experimental tools and represent potential treatments for patients with cardiomyopathy and muscular dystrophy.
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