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

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Screening of Transient Receptor Potential Canonical Channel Activators Identifies Novel Neurotrophic Piperazine Compounds S Supplemental material to this article can be found at: http://molpharm.aspetjournals.org/content/suppl/2016/01/05/mol.115.102863.DC1 1521-0111/89/3/348–363$25.00 http://dx.doi.org/10.1124/mol.115.102863 MOLECULAR PHARMACOLOGY Mol Pharmacol 89:348–363, March 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Screening of Transient Receptor Potential Canonical Channel Activators Identifies Novel Neurotrophic Piperazine Compounds s 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, and Yasuo Mori Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering (S.S., Ma.H., Y.T., H.H., Mi.H., R.R., S.K., M.X.M., Y.M.), and Department of Technology and Ecology, Hall of Global Environmental Studies (S.K., Y.M.), Kyoto Downloaded from University, Kyoto, Japan; Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan (Y.T., K.H., T.K., J.T., H.N., R.N.); Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan (A.N.); Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Japan (M.N.); and Department of Physiology, School of Medicine, Fukuoka University, Fukuoka, Japan (Y.H., R.I.) Received December 9, 2015; accepted January 4, 2016 molpharm.aspetjournals.org ABSTRACT Transient receptor potential canonical (TRPC) proteins form a dose-dependent manner, recombinant TRPC3/TRPC6/TRPC7 Ca21-permeable cation channels activated upon stimulation channels, but not other TRPCs, in human embryonic kidney cells. of metabotropic receptors coupled to phospholipase C. PPZ2 activated native TRPC6-like channels in smooth muscle Among the TRPC subfamily, TRPC3 and TRPC6 channels cells isolated from rabbit portal vein. Also, PPZ2 evoked cation activated directly by diacylglycerol (DAG) play important roles currents and Ca21 influx in rat cultured central neurons. Strikingly, in brain-derived neurotrophic factor (BDNF) signaling, promot- both compounds induced BDNF-like neurite growth and neuro- ing neuronal development and survival. In various disease protection, which were abolished by a knockdown or inhibition of at ASPET Journals on September 26, 2021 models, BDNF restores neurologic deficits, but its therapeutic TRPC3/TRPC6/TRPC7 in cultured neurons. Inhibitors of Ca21 potential is limited by its poor pharmacokinetic profile. Eluci- signaling pathways, except calcineurin, impaired neurite out- dation of a framework for designing small molecules, which growth promotion induced by PPZ compounds. PPZ2 increased elicit BDNF-like activity via TRPC3 and TRPC6, establishes a activation of the Ca21-dependent transcription factor, cAMP solid basis to overcome this limitation. We discovered, through response element–binding protein. These findings suggest library screening, a group of piperazine-derived compounds that that Ca21 signaling mediated by activation of DAG-activated activate DAG-activated TRPC3/TRPC6/TRPC7 channels. The TRPC channels underlies neurotrophic effects of PPZ com- compounds [4-(5-chloro-2-methylphenyl)piperazin-1-yl](3- pounds. Thus, piperazine-derived activators of DAG-activated fluorophenyl)methanone (PPZ1) and 2-[4-(2,3-dimethylphenyl)- TRPC channels provide important insights for future develop- piperazin-1-yl]-N-(2-ethoxyphenyl)acetamide (PPZ2) activated, in ment of a new class of synthetic neurotrophic drugs. Introduction Reichardt, 2003; Reichardt, 2006; Zhang et al., 2012). Through these intracellular signaling pathways, BDNF Brain-derived neurotrophic factor (BDNF) is the most abun- exerts neurotrophic functions, such as promoting neuronal dant and widely distributed neurotrophin in the mammalian growth and survival or modulating synaptic transmission central nervous system (CNS). BDNF binds to tropomyosin- and plasticity (Huang and Reichardt, 2001; Park and Poo, related kinase B, a receptor tyrosine kinase, to stimulate 2013). BDNF administration showed beneficial effects in various intracellular signaling pathways mediated by models for various diseases, such as Alzheimer’sdisease, mitogen-activated protein kinase (MAPK), phosphatidylino- Parkinson’s disease, depression, and schizophrenia (Nagahara sitol 3-kinase, or phospholipase C (PLC) g (Huang and and Tuszynski, 2011; Autry and Monteggia, 2012). However, its pharmacokinetic properties, including short plasma half- This work was supported by a Grant-in-Aid for Scientific Research on life and poor blood-brain barrier penetration, limit its thera- Innovative Areas “Oxygen Biology: A New Criterion for Integrated Un- derstanding of Life” [Grant 26111004] of The Ministry of Education, Culture, peutic applications (Poduslo and Curran, 1996). Therefore, Sports, Science and Technology, Japan; and a Grant-in-Aid for Scientific discovery of small molecules that mimic the neurotrophic Research (A) [Grant 24249017] of Japan Society for the Promotion of Science. actions of BDNF would be a promising therapeutic strategy This work was funded by Sumitomo Dainippon Pharma Co., Ltd. Y.T., K.H., T.K., J.T., H.N., and R.N. were full-time employees of Sumitomo Dainippon for neurologic and psychiatric disorders. Pharma Co., Ltd., when this study was conducted. Drosophila melanogaster transient receptor potential (TRP) dx.doi.org/10.1124/mol.115.102863. s This article has supplemental material available at (molpharm. protein and its homologs are putative six-transmembrane 21 aspetjournals.org). polypeptide subunits that form tetrameric Ca -permeable 348 Neurotrophic Action of Novel TRPC Channel Activators 349 nonselective cation channels (Clapham, 2003; Clapham et al., molecular functions and exerts various beneficial effects, 2005; Nilius and Szallasi, 2014). Mammalian TRP channels showing antimicrobial, anti-inflammatory, anticancer, and are grouped into six related subfamilies: TRP “canonical” antidepressant activity (Russo et al., 2014). It has been pre- (TRPC), TRP “vanilloid” (TRPV), TRP “melastatin” (TRPM), viously reported that hyperforin exerts antidepressant and TRP “ankyrin” (TRPA), TRP “polycystin”, and TRP “mucolipin. neurotrophic effects via activation of TRPC6 in neurons (Leuner TRP channels are activated by diverse stimuli, including et al., 2007, 2013; Griesi-Oliveira et al., 2015). However, the receptor stimulation, heat, osmotic pressure, mechanical activity of hyperforin remains controversial: a recent publica- stress, and environmental irritants from the extracellular and tion implicates that the protonophore activity of hyperforin intracellular milieu. The TRPC subfamily comprises seven contributes to its pharmacological effects (Sell et al., 2014). members (TRPC1–C7), highly expressed in the mammalian CNS These insights support the concept that activation of DAG- and mediating cation influx induced by activation of PLC-coupled activated TRPC3 and TRPC6 channels are potential thera- metabotropic receptors, such as G protein–coupled receptors and peutic approaches for neurologic and psychiatric disorders. receptor tyrosine kinases (Vazquez et al., 2004; Abramowitz and However, a framework for designing small molecules that Birnbaumer, 2009). PLC hydrolyzes phosphatidylinositol activate DAG-activated TRPC channels, thus inducing 4,5-bisphosphate to form diacylglycerol (DAG) (Fig. 1A) and neurotrophic effects on CNS, remains to be discovered. In this study, we identified small-molecule activators of inositol 1,4,5-trisphosphate. In addition to their well known Downloaded from activation of protein kinase C (PKC), a kinase regulating a DAG-activated TRPC3, TRPC6, and TRPC7 channels which plethora of biologic functions (Nishizuka, 1995), DAG and its showed trophic effects on neurons. Using a high-throughput analogs also activate the closely related TRPC subtypes: screening assay, we identified nine piperazine derivatives by TRPC3, TRPC6, and TRPC7 (Hofmann et al., 1999). monitoring depolarizing effects on membrane potential in In the CNS, TRPC3 and TRPC6 modulate neurotransmis- human embryonic kidney (HEK) cells expressing recombinant sion, synaptic plasticity, neuronal development, and neuronal TRPC channels (Fig. 1B). Two piperazine compounds desig- molpharm.aspetjournals.org survival (Abramowitz and Birnbaumer, 2009; Nilius and nated as PPZ1 ([4-(5-chloro-2-methylphenyl)piperazin-1-yl](3- Szallasi, 2014). Previous studies further showed that TRPC3 fluorophenyl)methanone) and PPZ2 (2-[4-(2,3-dimethylphenyl) and TRPC6 are important for growth cone turning, spine piperazin-1-yl]-N-(2-ethoxyphenyl)acetamide) potently acti- formation, and neuronal survival induced by BDNF stimula- vated TRPC3, TRPC6, and TRPC7 among TRPC subfamily and promoted neurite outgrowth and neuronal survival via tion in neurons (Li et al., 2005; Amaral and Pozzo-Miller, 2007; 21 Jia et al., 2007). It has been suggested that, with BDNF downstream Ca -dependent signals. These findings clearly stimulation, TRPC3 and TRPC6 are activated by the PLC support the potential of novel small-molecule mimics of BDNF – 21 pathway via tropomyosin-related kinase B (Li et al., 1999, that target TRPC channel dependent Ca signaling as an important basis to develop leads of therapeutic drugs for Amaral and Pozzo-Miller, 2007; Jia et al.,
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