Screening of Transient Receptor Potential Canonical Channel Activators Identifies Novel Neurotrophic Piperazine Compoundss

Seishiro Sawamura, Masahiko Hatano, Yoshinori Takada, Kyosuke Hino, Tetsuya Kawamura, Jun Tanikawa, Hiroshi Nakagawa, Hideharu Hase, Akito Nakao, Mitsuru Hirano, Rachapun Rotrattanadumrong, Shigeki Kiyonaka, Masayuki X. Mori, Motohiro Nishida, Yaopeng Hu, Ryuji Inoue, Ryu Nagata, Yasuo Mori

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Transient receptor potential canonical (TRPC) proteins form Ca2+ -permeable cation channels activated upon stimulation of metabotropic receptors coupled to phospholipase C. Among the TRPC subfamily, TRPC3 and TRPC6 channels activated directly by diacylglycerol (DAG) play important roles in brain-derived neurotrophic factor (BDNF) signaling, promoting neuronal development and survival. In various disease models, BDNF restores neurologic deficits, but its therapeutic potential is limited by its poor pharmacokinetic profile. Elucidation of a framework for designing small molecules, which elicit BDNF-like activity via TRPC3 and TRPC6, establishes a solid basis to overcome this limitation. We discovered, through library screening, a group of piperazine-derived compounds that activate DAG-activated TRPC3/TRPC6/TRPC7 channels. The compounds [4-(5-chloro-2-methylphenyl)piperazin-1-yl](3-fluorophenyl)methanone (PPZ1) and 2-[4-(2,3-dimethylphenyl)-piperazin-1-yl]-N-(2-ethoxyphenyl)acetamide (PPZ2) activated, in a dose-dependent manner, recombinant TRPC3/TRPC6/TRPC7 channels, but not other TRPCs, in human embryonic kidney cells. PPZ2 activated native TRPC6-like channels in smooth muscle cells isolated from rabbit portal vein. Also, PPZ2 evoked cation currents and Ca2+ influx in rat cultured central neurons. Strikingly, both compounds induced BDNF-like neurite growth and neuroprotection, which were abolished by a knockdown or inhibition of TRPC3/TRPC6/TRPC7 in cultured neurons. Inhibitors of Ca2+ signaling pathways, except calcineurin, impaired neurite outgrowth promotion induced by PPZ compounds. PPZ2 increased activation of the Ca2+ -dependent transcription factor, cAMP response element-binding protein. These findings suggest that Ca2+ signaling mediated by activation of DAG-activated TRPC channels underlies neurotrophic effects of PPZ compounds. Thus, piperazine-derived activators of DAG-activated TRPC channels provide important insights for future development of a new class of synthetic neurotrophic drugs.

Original languageEnglish
Pages (from-to)348-363
Number of pages16
JournalMolecular Pharmacology
Volume89
Issue number3
DOIs
Publication statusPublished - 01-03-2016

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Transient Receptor Potential Channels
Diglycerides
Brain-Derived Neurotrophic Factor
Cations
Neurons
Cyclic AMP Response Element-Binding Protein
Calcineurin
Type C Phospholipases
Neurites
Neurologic Manifestations
Portal Vein
Smooth Muscle Myocytes
Transcription Factors
Pharmacokinetics
Rabbits
Kidney
Survival
piperazine
Growth
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Sawamura, Seishiro ; Hatano, Masahiko ; Takada, Yoshinori ; Hino, Kyosuke ; Kawamura, Tetsuya ; Tanikawa, Jun ; Nakagawa, Hiroshi ; Hase, Hideharu ; Nakao, Akito ; Hirano, Mitsuru ; Rotrattanadumrong, Rachapun ; Kiyonaka, Shigeki ; Mori, Masayuki X. ; Nishida, Motohiro ; Hu, Yaopeng ; Inoue, Ryuji ; Nagata, Ryu ; Mori, Yasuo. / Screening of Transient Receptor Potential Canonical Channel Activators Identifies Novel Neurotrophic Piperazine Compoundss. In: Molecular Pharmacology. 2016 ; Vol. 89, No. 3. pp. 348-363.
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Sawamura, S, Hatano, M, Takada, Y, Hino, K, Kawamura, T, Tanikawa, J, Nakagawa, H, Hase, H, Nakao, A, Hirano, M, Rotrattanadumrong, R, Kiyonaka, S, Mori, MX, Nishida, M, Hu, Y, Inoue, R, Nagata, R & Mori, Y 2016, 'Screening of Transient Receptor Potential Canonical Channel Activators Identifies Novel Neurotrophic Piperazine Compoundss', Molecular Pharmacology, vol. 89, no. 3, pp. 348-363. https://doi.org/10.1124/mol.115.102863

Screening of Transient Receptor Potential Canonical Channel Activators Identifies Novel Neurotrophic Piperazine Compoundss. / Sawamura, Seishiro; Hatano, Masahiko; Takada, Yoshinori; Hino, Kyosuke; Kawamura, Tetsuya; Tanikawa, Jun; Nakagawa, Hiroshi; Hase, Hideharu; Nakao, Akito; Hirano, Mitsuru; Rotrattanadumrong, Rachapun; Kiyonaka, Shigeki; Mori, Masayuki X.; Nishida, Motohiro; Hu, Yaopeng; Inoue, Ryuji; Nagata, Ryu; Mori, Yasuo.

In: Molecular Pharmacology, Vol. 89, No. 3, 01.03.2016, p. 348-363.

Research output: Contribution to journalArticle

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AU - Sawamura, Seishiro

AU - Hatano, Masahiko

AU - Takada, Yoshinori

AU - Hino, Kyosuke

AU - Kawamura, Tetsuya

AU - Tanikawa, Jun

AU - Nakagawa, Hiroshi

AU - Hase, Hideharu

AU - Nakao, Akito

AU - Hirano, Mitsuru

AU - Rotrattanadumrong, Rachapun

AU - Kiyonaka, Shigeki

AU - Mori, Masayuki X.

AU - Nishida, Motohiro

AU - Hu, Yaopeng

AU - Inoue, Ryuji

AU - Nagata, Ryu

AU - Mori, Yasuo

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N2 - Transient receptor potential canonical (TRPC) proteins form Ca2+ -permeable cation channels activated upon stimulation of metabotropic receptors coupled to phospholipase C. Among the TRPC subfamily, TRPC3 and TRPC6 channels activated directly by diacylglycerol (DAG) play important roles in brain-derived neurotrophic factor (BDNF) signaling, promoting neuronal development and survival. In various disease models, BDNF restores neurologic deficits, but its therapeutic potential is limited by its poor pharmacokinetic profile. Elucidation of a framework for designing small molecules, which elicit BDNF-like activity via TRPC3 and TRPC6, establishes a solid basis to overcome this limitation. We discovered, through library screening, a group of piperazine-derived compounds that activate DAG-activated TRPC3/TRPC6/TRPC7 channels. The compounds [4-(5-chloro-2-methylphenyl)piperazin-1-yl](3-fluorophenyl)methanone (PPZ1) and 2-[4-(2,3-dimethylphenyl)-piperazin-1-yl]-N-(2-ethoxyphenyl)acetamide (PPZ2) activated, in a dose-dependent manner, recombinant TRPC3/TRPC6/TRPC7 channels, but not other TRPCs, in human embryonic kidney cells. PPZ2 activated native TRPC6-like channels in smooth muscle cells isolated from rabbit portal vein. Also, PPZ2 evoked cation currents and Ca2+ influx in rat cultured central neurons. Strikingly, both compounds induced BDNF-like neurite growth and neuroprotection, which were abolished by a knockdown or inhibition of TRPC3/TRPC6/TRPC7 in cultured neurons. Inhibitors of Ca2+ signaling pathways, except calcineurin, impaired neurite outgrowth promotion induced by PPZ compounds. PPZ2 increased activation of the Ca2+ -dependent transcription factor, cAMP response element-binding protein. These findings suggest that Ca2+ signaling mediated by activation of DAG-activated TRPC channels underlies neurotrophic effects of PPZ compounds. Thus, piperazine-derived activators of DAG-activated TRPC channels provide important insights for future development of a new class of synthetic neurotrophic drugs.

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