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; Jin Nakahara; Tetsuya Suhara; Masahiko Takada; Makoto Higuchi; Jian Jin; Bryan L Roth; Takafumi Minamimoto

doi:10.1038/s41593-020-0661-3

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

Nat Neurosci. 2020 Sep;23(9):1157-1167. doi: 10.1038/s41593-020-0661-3. Epub 2020 Jul 6.

Authors

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

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Behavior, Animal / drug effects*
Brain / drug effects*
Clozapine / analogs & derivatives*
Clozapine / pharmacology
Designer Drugs / pharmacology*
Genetic Techniques
Humans
Macaca fuscata
Macaca mulatta
Mice
Mice, Inbred C57BL
Mice, Transgenic
Models, Animal
Neurons / drug effects*
Receptor, Muscarinic M3 / metabolism
Receptor, Muscarinic M4 / metabolism

Substances

Designer Drugs
Receptor, Muscarinic M3
Receptor, Muscarinic M4
11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4)diazepine
Clozapine

Abstract

Publication types

MeSH terms

Substances

Grants and funding