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

Yuji Nagai^#¹, Naohisa Miyakawa^#¹, Hiroyuki Takuwa¹, Yukiko Hori¹, Kei Oyama¹, Bin Ji¹, Manami Takahashi¹, Xi-Ping Huang^{2

3}, Samuel T Slocum², Jeffrey F DiBerto², Yan Xiong⁴, Takuya Urushihata¹, Toshiyuki Hirabayashi¹, Atsushi Fujimoto¹, Koki Mimura¹, Justin G English², Jing Liu⁴, Ken-Ichi Inoue^{5

6}, Katsushi Kumata⁷, Chie Seki¹, Maiko Ono¹, Masafumi Shimojo¹, Ming-Rong Zhang⁷, Yutaka Tomita⁸, Jin Nakahara⁸, Tetsuya Suhara¹, Masahiko Takada⁵, Makoto Higuchi¹, Jian Jin⁴, Bryan L Roth^{9

10

11}, Takafumi Minamimoto¹²

Affiliations

¹ Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
² Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
³ Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ 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, USA.
⁵ Systems Neuroscience Section, Primate Research Institute, Kyoto University, Inuyama, Japan.
⁶ PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan.
⁷ Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
⁸ Department of Neurology, Keio University School of Medicine, Tokyo, Japan.
⁹ Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. bryan_roth@med.unc.edu.
¹⁰ Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. bryan_roth@med.unc.edu.
¹¹ National 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, USA. bryan_roth@med.unc.edu.
¹² Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan. minamimoto.takafumi@qst.go.jp.

^# Contributed equally.

PMID: 32632286
DOI: 10.1038/s41593-020-0661-3

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

Yuji Nagai et al. Nat Neurosci. 2020 Sep.

. 2020 Sep;23(9):1157-1167.

doi: 10.1038/s41593-020-0661-3. Epub 2020 Jul 6.

Authors

Affiliations

¹ Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
² Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
³ Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ 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, USA.
⁵ Systems Neuroscience Section, Primate Research Institute, Kyoto University, Inuyama, Japan.
⁶ PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan.
⁷ Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
⁸ Department of Neurology, Keio University School of Medicine, Tokyo, Japan.
⁹ Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. bryan_roth@med.unc.edu.
¹⁰ Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. bryan_roth@med.unc.edu.
¹¹ National 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, USA. bryan_roth@med.unc.edu.
¹² Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan. minamimoto.takafumi@qst.go.jp.

^# Contributed equally.

PMID: 32632286
DOI: 10.1038/s41593-020-0661-3

Abstract

The chemogenetic technology designer receptors exclusively activated by designer drugs (DREADDs) afford remotely reversible control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities and potential off-target effects of CNO represent areas for improvement. Here, we provide a new high-affinity and selective agonist deschloroclozapine (DCZ) 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 per kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 μg per kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents a potent, selective, metabolically stable and fast-acting DREADD agonist with utility in both mice and nonhuman primates for a variety of applications.

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References

1. Armbruster, B. N., Li, X., Pausch, M. H., Herlitze, S. & Roth, B. L. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc. Natl Acad. Sci. USA 104, 5163–5168 (2007). - PubMed - DOI - PMC
1. Vardy, E. et al. A new DREADD facilitates the multiplexed chemogenetic interrogation of behavior. Neuron 86, 936–946 (2015). - PubMed - PMC - DOI
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1. Eldridge, M. A. G. et al. Chemogenetic disconnection of monkey orbitofrontal and rhinal cortex reversibly disrupts reward value. Nat. Neurosci. 19, 37–39 (2015). - PubMed - PMC - DOI

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

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

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Abstract

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