Screening of Transient Receptor Potential Canonical Channel Activators Identifies Novel Neurotrophic Piperazine Compounds
| Autor: | Hiroshi Nakagawa, Hideharu Hase, Seishiro Sawamura, Masayuki X. Mori, Kyosuke Hino, Akito Nakao, Ryuji Inoue, Jun Tanikawa, Shigeki Kiyonaka, Mitsuru Hirano, Yaopeng Hu, Rachapun Rotrattanadumrong, Yasuo Mori, Motohiro Nishida, Ryu Nagata, Masahiko Hatano, Yoshinori Takada, Tetsuya Kawamura |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Neurite Myocytes Smooth Muscle Drug Evaluation Preclinical Pharmacology Biology TRPC5 Piperazines Membrane Potentials TRPC6 03 medical and health sciences Transient receptor potential channel TRPC3 Neurotrophic factors Animals Humans Calcium Signaling Nerve Growth Factors Rats Wistar TRPC TRPC Cation Channels Rats Cell biology HEK293 Cells 030104 developmental biology Molecular Medicine Female Rabbits Signal transduction |
| Zdroj: | Molecular Pharmacology. 89:348-363 |
| ISSN: | 1521-0111 0026-895X |
| DOI: | 10.1124/mol.115.102863 |
| Popis: | Transient receptor potential canonical (TRPC) proteins form Ca(2+)-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 Ca(2+) 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 Ca(2+) signaling pathways, except calcineurin, impaired neurite outgrowth promotion induced by PPZ compounds. PPZ2 increased activation of the Ca(2+)-dependent transcription factor, cAMP response element-binding protein. These findings suggest that Ca(2+) 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. |
| Databáze: | OpenAIRE |
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