title: Identification and optimization of 2-aminobenzimidazole derivatives as novel inhibitors of TRPC4 and TRPC5 channels.
abstract: OBJECTIVE
  Transient receptor potential canonical (TRPC) channels play important roles in a broad array of physiological functions and are involved in various diseases. However, due to a lack of potent subtype-specific inhibitors the exact roles of TRPC channels in physiological and pathophysiological conditions have not been elucidated.
  
  
  METHODS
  Using fluorescence membrane potential and Ca(2+) assays and electrophysiological recordings, we characterized new 2-aminobenzimidazole-based small molecule inhibitors of TRPC4 and TRPC5 channels identified from cell-based fluorescence high-throughput screening.
  
  
  RESULTS
  The original compound, M084, was a potent inhibitor of both TRPC4 and TRPC5, but was also a weak inhibitor of TRPC3. Structural modifications of the lead compound resulted in the identification of analogues with improved potency and selectivity for TRPC4 and TRPC5 channels. The aminobenzimidazole derivatives rapidly inhibited the TRPC4- and TRPC5-mediated currents when applied from the extracellular side and this inhibition was independent of the mode of activation of these channels. The compounds effectively blocked the plateau potential mediated by TRPC4-containing channels in mouse lateral septal neurons, but did not affect the activity of heterologously expressed TRPA1, TRPM8, TRPV1 or TRPV3 channels or that of the native voltage-gated Na(+) , K(+) and Ca(2) (+) channels in dissociated neurons.
  
  
  CONCLUSIONS
  The TRPC4/C5-selective inhibitors developed here represent novel and useful pharmaceutical tools for investigation of physiological and pathophysiological functions of TRPC4/C5 channels.
authors: Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors: Yingmin
authors: Y
authors: Zhu
authors: Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, USA.|The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors: Yungang
authors: Y
authors: Lu
authors: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, Hubei, China.
authors: Chunrong
authors: C
authors: Qu
authors: Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Melissa
authors: M
authors: Miller
authors: Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors: Jinbin
authors: J
authors: Tian
authors: Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors: Dhananjay P
authors: DP
authors: Thakur
authors: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, Hubei, China.
authors: Jinmei
authors: J
authors: Zhu
authors: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, Hubei, China.
authors: Zixin
authors: Z
authors: Deng
authors: The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors: Xianming
authors: X
authors: Hu
authors: Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Meng
authors: M
authors: Wu
authors: Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Owen B
authors: OB
authors: McManus
authors: Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Min
authors: M
authors: Li
authors: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, Wuhan University School of Pharmaceutical Sciences, Wuhan, Hubei, China.
authors: Xuechuan
authors: X
authors: Hong
authors: Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors: Michael X
authors: MX
authors: Zhu
authors: State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, The Chinese Academy of Sciences, Kunming, Yunnan, China.
authors: Huai-Rong
authors: HR
authors: Luo
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; C491780:TRPC5 protein, human; C027391:2-aminobenzimidazole