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

Yingmin Zhu, Yungang Lu, Chunrong Qu, Melissa Miller, Jinbin Tian, Dhananjay P. Thakur, Jinmei Zhu, Zixin Deng, Xianming Hu, Meng Wu, Owen B. McManus, Min Li, Xuechuan Hong, Michael X. Zhu, Huai Rong Luo

Research output: Contribution to journalArticle

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 Ca2+ 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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)3495-3509
Number of pages15
JournalBritish Journal of Pharmacology
Volume172
Issue number14
DOIs
StatePublished - Jul 1 2015

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Transient Receptor Potential Channels
Fluorescence
Neurons
Membrane Potentials
Pharmaceutical Preparations
2-aminobenzimidazole
Lead

ASJC Scopus subject areas

  • Pharmacology

Cite this

Identification and optimization of 2-aminobenzimidazole derivatives as novel inhibitors of TRPC4 and TRPC5 channels. / Zhu, Yingmin; Lu, Yungang; Qu, Chunrong; Miller, Melissa; Tian, Jinbin; Thakur, Dhananjay P.; Zhu, Jinmei; Deng, Zixin; Hu, Xianming; Wu, Meng; McManus, Owen B.; Li, Min; Hong, Xuechuan; Zhu, Michael X.; Luo, Huai Rong.

In: British Journal of Pharmacology, Vol. 172, No. 14, 01.07.2015, p. 3495-3509.

Research output: Contribution to journalArticle

Zhu, Y, Lu, Y, Qu, C, Miller, M, Tian, J, Thakur, DP, Zhu, J, Deng, Z, Hu, X, Wu, M, McManus, OB, Li, M, Hong, X, Zhu, MX & Luo, HR 2015, 'Identification and optimization of 2-aminobenzimidazole derivatives as novel inhibitors of TRPC4 and TRPC5 channels', British Journal of Pharmacology, vol. 172, no. 14, pp. 3495-3509. https://doi.org/10.1111/bph.13140
Zhu, Yingmin ; Lu, Yungang ; Qu, Chunrong ; Miller, Melissa ; Tian, Jinbin ; Thakur, Dhananjay P. ; Zhu, Jinmei ; Deng, Zixin ; Hu, Xianming ; Wu, Meng ; McManus, Owen B. ; Li, Min ; Hong, Xuechuan ; Zhu, Michael X. ; Luo, Huai Rong. / Identification and optimization of 2-aminobenzimidazole derivatives as novel inhibitors of TRPC4 and TRPC5 channels. In: British Journal of Pharmacology. 2015 ; Vol. 172, No. 14. pp. 3495-3509.
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AU - Zhu, Yingmin

AU - Lu, Yungang

AU - Qu, Chunrong

AU - Miller, Melissa

AU - Tian, Jinbin

AU - Thakur, Dhananjay P.

AU - Zhu, Jinmei

AU - Deng, Zixin

AU - Hu, Xianming

AU - Wu, Meng

AU - McManus, Owen B.

AU - Li, Min

AU - Hong, Xuechuan

AU - Zhu, Michael X.

AU - Luo, Huai Rong

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N2 - 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 Ca2+ 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 Ca2+ 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.

AB - 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 Ca2+ 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 Ca2+ 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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