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

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  • Nagai, Y.
    • Other Affiliation: National Institutes for Quantum and Radiological Science and Technology
  • Miyakawa, N.
    • Other Affiliation: National Institutes for Quantum and Radiological Science and Technology
  • Takuwa, H.
    • Other Affiliation: National Institutes for Quantum and Radiological Science and Technology
  • Hori, Y.
    • Other Affiliation: National Institutes for Quantum and Radiological Science and Technology
  • Oyama, K.
    • Other Affiliation: National Institutes for Quantum and Radiological Science and Technology
  • Ji, B.
    • Other Affiliation: National Institutes for Quantum and Radiological Science and Technology
  • Takahashi, M.
    • Other Affiliation: National Institutes for Quantum and Radiological Science and Technology
  • Huang, X.-P.
    • School of Medicine, Department of Pharmacology
  • Slocum, S.T.
    • School of Medicine, Department of Pharmacology
  • DiBerto, J.F.
    • School of Medicine, Department of Pharmacology
  • Xiong, Y.
    • Other Affiliation: Icahn School of Medicine at Mount Sinai
  • Urushihata, T.
    • Other Affiliation: National Institutes for Quantum and Radiological Science and Technology
  • Hirabayashi, T.
    • Other Affiliation: National Institutes for Quantum and Radiological Science and Technology
  • Fujimoto, A.
    • Other Affiliation: National Institutes for Quantum and Radiological Science and Technology
  • Mimura, K.
    • Other Affiliation: National Institutes for Quantum and Radiological Science and Technology
  • English, J.G.
    • School of Medicine, Department of Pharmacology
  • Liu, J.
    • Other Affiliation: Icahn School of Medicine at Mount Sinai
  • Inoue, K.-I.
    • Other Affiliation: Kyoto University
  • Kumata, K.
    • Other Affiliation: National Institutes for Quantum and Radiological Science and Technology
  • Seki, C.
    • Other Affiliation: National Institutes for Quantum and Radiological Science and Technology
  • Ono, M.
    • Other Affiliation: National Institutes for Quantum and Radiological Science and Technology
  • Shimojo, M.
    • Other Affiliation: National Institutes for Quantum and Radiological Science and Technology
  • Zhang, M.-R.
    • Other Affiliation: National Institutes for Quantum and Radiological Science and Technology
  • Tomita, Y.
    • Other Affiliation: Keio University School of Medicine
  • Nakahara, J.
    • Other Affiliation: Keio University School of Medicine
  • Suhara, T.
    • Other Affiliation: National Institutes for Quantum and Radiological Science and Technology
  • Takada, M.
    • Other Affiliation: Kyoto University
  • Higuchi, M.
    • Other Affiliation: National Institutes for Quantum and Radiological Science and Technology
  • Jin, J.
    • Other Affiliation: Icahn School of Medicine at Mount Sinai
  • Roth, B.L.
    • School of Medicine, Department of Pharmacology
  • Minamimoto, T.
    • Other Affiliation: National Institutes for Quantum and Radiological Science and Technology
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.
Date of publication
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DOI
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Resource type
  • Article
Rights statement
  • In Copyright
Journal title
  • Nature Neuroscience
Journal volume
  • 23
Journal issue
  • 9
Page start
  • 1157
Page end
  • 1167
Language
  • English
ISSN
  • 1097-6256
Publisher
  • Nature Research

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