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Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys.
Nagai, Yuji; Miyakawa, Naohisa; Takuwa, Hiroyuki; Hori, Yukiko; Oyama, Kei; Ji, Bin; Takahashi, Manami; Huang, Xi-Ping; Slocum, Samuel T; DiBerto, Jeffrey F; Xiong, Yan; Urushihata, Takuya; Hirabayashi, Toshiyuki; Fujimoto, Atsushi; Mimura, Koki; English, Justin G; Liu, Jing; Inoue, Ken-Ichi; Kumata, Katsushi; Seki, Chie; Ono, Maiko; Shimojo, Masafumi; Zhang, Ming-Rong; Tomita, Yutaka; Nakahara, Jin; Suhara, Tetsuya; Takada, Masahiko; Higuchi, Makoto; Jin, Jian; Roth, Bryan L; Minamimoto, Takafumi.
Afiliação
  • Nagai Y; Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
  • Miyakawa N; Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
  • Takuwa H; Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
  • Hori Y; Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
  • Oyama K; Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
  • Ji B; Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
  • Takahashi M; Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
  • Huang XP; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Slocum ST; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • DiBerto JF; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Xiong Y; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Urushihata T; 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.
  • Hirabayashi T; Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
  • Fujimoto A; Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
  • Mimura K; Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
  • English JG; Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
  • Liu J; Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
  • Inoue KI; 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.
  • Kumata K; Systems Neuroscience Section, Primate Research Institute, Kyoto University, Inuyama, Japan.
  • Seki C; PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan.
  • Ono M; Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
  • Shimojo M; Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
  • Zhang MR; Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
  • Tomita Y; Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
  • Nakahara J; Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
  • Suhara T; Department of Neurology, Keio University School of Medicine, Tokyo, Japan.
  • Takada M; Department of Neurology, Keio University School of Medicine, Tokyo, Japan.
  • Higuchi M; Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
  • Jin J; Systems Neuroscience Section, Primate Research Institute, Kyoto University, Inuyama, Japan.
  • Roth BL; Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
  • Minamimoto T; 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.
Nat Neurosci ; 23(9): 1157-1167, 2020 09.
Article em En | MEDLINE | ID: mdl-32632286
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Comportamento Animal / Encéfalo / Drogas Desenhadas / Clozapina / Neurônios Limite: Animals / Humans Idioma: En Revista: Nat Neurosci Assunto da revista: NEUROLOGIA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Japão
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Comportamento Animal / Encéfalo / Drogas Desenhadas / Clozapina / Neurônios Limite: Animals / Humans Idioma: En Revista: Nat Neurosci Assunto da revista: NEUROLOGIA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Japão