2. Academic Validation
  3. Identification and optimization of 2-aminobenzimidazole derivatives as novel inhibitors of TRPC4 and TRPC5 channels

Identification and optimization of 2-aminobenzimidazole derivatives as novel inhibitors of TRPC4 and TRPC5 channels

  • Br J Pharmacol. 2015 Jul;172(14):3495-509. doi: 10.1111/bph.13140.
Yingmin Zhu 1,  Yungang Lu 1 2,  Chunrong Qu 3,  Melissa Miller 4,  Jinbin Tian 1,  Dhananjay P Thakur 1,  Jinmei Zhu 3,  Zixin Deng 3,  Xianming Hu 2,  Meng Wu 4,  Owen B McManus 4,  Min Li 4,  Xuechuan Hong 3,  Michael X Zhu 1,  Huai-Rong Luo 5
Affiliations

Affiliations

  • 1 Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 2 The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 3 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.
  • 4 Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 5 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, The Chinese Academy of Sciences, Kunming, Yunnan, China.
PMID: 25816897 DOI: 10.1111/bph.13140
Abstract

Background and purpose: 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.

Experimental approach: 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.

Key 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 and implications: The TRPC4/C5-selective inhibitors developed here represent novel and useful pharmaceutical tools for investigation of physiological and pathophysiological functions of TRPC4/C5 channels.

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