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Deschloroclozapine: a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys

View ORCID ProfileYuji Nagai, View ORCID ProfileNaohisa Miyakawa, Hiroyuki Takuwa, Yukiko Hori, Kei Oyama, Bin Ji, Manami Takahashi, View ORCID ProfileXi-Ping Huang, Samuel T. Slocum, Jeffrey F. DiBerto, Yan Xiong, Takuya Urushihata, Toshiyuki Hirabayashi, View ORCID ProfileAtsushi Fujimoto, Koki Mimura, View ORCID ProfileJustin G. English, Jing Liu, Ken-ichi Inoue, Katsushi Kumata, Chie Seki, Maiko Ono, Masafumi Shimojo, Ming-Rong Zhang, Yutaka Tomita, View ORCID ProfileTetsuya Suhara, Masahiko Takada, Makoto Higuchi, Jian Jin, Bryan L. Roth, View ORCID ProfileTakafumi Minamimoto
doi: https://doi.org/10.1101/854513
Yuji Nagai
Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan
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Naohisa Miyakawa
Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan
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  • ORCID record for Naohisa Miyakawa
Hiroyuki Takuwa
Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan
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Yukiko Hori
Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan
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Kei Oyama
Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan
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Bin Ji
Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan
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Manami Takahashi
Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan
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Xi-Ping Huang
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27514, U.S.A.Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
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Samuel T. Slocum
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27514, U.S.A.
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Jeffrey F. DiBerto
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27514, U.S.A.
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Yan Xiong
Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 U.S.A.
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Takuya Urushihata
Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan
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Toshiyuki Hirabayashi
Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan
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Atsushi Fujimoto
Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan
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Koki Mimura
Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan
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Justin G. English
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27514, U.S.A.
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  • ORCID record for Justin G. English
Jing Liu
Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 U.S.A.
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Ken-ichi Inoue
Systems Neuroscience Section, Primate Research Institute, Kyoto University, Inuyama, Aichi 484-8506, JapanPRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan
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Katsushi Kumata
Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan
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Chie Seki
Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan
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Maiko Ono
Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan
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Masafumi Shimojo
Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan
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Ming-Rong Zhang
Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan
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Yutaka Tomita
Depaprment of Neurology, Keio University School of Medicine, Tokyo 160-8582, Japan
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Tetsuya Suhara
Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan
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Masahiko Takada
Systems Neuroscience Section, Primate Research Institute, Kyoto University, Inuyama, Aichi 484-8506, Japan
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Makoto Higuchi
Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan
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Jian Jin
Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 U.S.A.
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Bryan L. Roth
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27514, U.S.A.Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USANational Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), Department of Pharmacology, University of North Carolina at Chapel Hill Medical School, Chapel Hill, NC 27514, USA
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  • For correspondence: minamimoto.takafumi@qst.go.jp bryan_roth@med.unc.edu
Takafumi Minamimoto
Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555 Japan
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  • ORCID record for Takafumi Minamimoto
  • For correspondence: minamimoto.takafumi@qst.go.jp bryan_roth@med.unc.edu
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ABSTRACT

The chemogenetic technology, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), affords reversible and remote control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, the sluggish kinetics, metabolic liabilities, and potential for off-target effects of CNO represent areas for improvement. Here we provide a new agonist deschloroclozapine (DCZ), which displays high affinity and selectivity for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 μg/kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injection of DCZ (100 μg/kg) reversibly induced behavioral deficits in hM4Di-expressing monkeys. DCZ represents the most potent, selective, metabolically stable and fast-acting DREADD agonist reported with utility in both mice and non-human primates for a variety of applications.

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Posted December 03, 2019.
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Deschloroclozapine: a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys
Yuji Nagai, Naohisa Miyakawa, Hiroyuki Takuwa, Yukiko Hori, Kei Oyama, Bin Ji, Manami Takahashi, Xi-Ping Huang, Samuel T. Slocum, Jeffrey F. DiBerto, Yan Xiong, Takuya Urushihata, Toshiyuki Hirabayashi, Atsushi Fujimoto, Koki Mimura, Justin G. English, Jing Liu, Ken-ichi Inoue, Katsushi Kumata, Chie Seki, Maiko Ono, Masafumi Shimojo, Ming-Rong Zhang, Yutaka Tomita, Tetsuya Suhara, Masahiko Takada, Makoto Higuchi, Jian Jin, Bryan L. Roth, Takafumi Minamimoto
bioRxiv 854513; doi: https://doi.org/10.1101/854513
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Deschloroclozapine: a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys
Yuji Nagai, Naohisa Miyakawa, Hiroyuki Takuwa, Yukiko Hori, Kei Oyama, Bin Ji, Manami Takahashi, Xi-Ping Huang, Samuel T. Slocum, Jeffrey F. DiBerto, Yan Xiong, Takuya Urushihata, Toshiyuki Hirabayashi, Atsushi Fujimoto, Koki Mimura, Justin G. English, Jing Liu, Ken-ichi Inoue, Katsushi Kumata, Chie Seki, Maiko Ono, Masafumi Shimojo, Ming-Rong Zhang, Yutaka Tomita, Tetsuya Suhara, Masahiko Takada, Makoto Higuchi, Jian Jin, Bryan L. Roth, Takafumi Minamimoto
bioRxiv 854513; doi: https://doi.org/10.1101/854513

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