1. Academic Validation
  2. Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys

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.
Yuji Nagai  # 1 Naohisa Miyakawa  # 1 Hiroyuki Takuwa 1 Yukiko Hori 1 Kei Oyama 1 Bin Ji 1 Manami Takahashi 1 Xi-Ping Huang 2 3 Samuel T Slocum 2 Jeffrey F DiBerto 2 Yan Xiong 4 Takuya Urushihata 1 Toshiyuki Hirabayashi 1 Atsushi Fujimoto 1 Koki Mimura 1 Justin G English 2 Jing Liu 4 Ken-Ichi Inoue 5 6 Katsushi Kumata 7 Chie Seki 1 Maiko Ono 1 Masafumi Shimojo 1 Ming-Rong Zhang 7 Yutaka Tomita 8 Jin Nakahara 8 Tetsuya Suhara 1 Masahiko Takada 5 Makoto Higuchi 1 Jian Jin 4 Bryan L Roth 9 10 11 Takafumi Minamimoto 12
Affiliations

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.
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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