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

Animals Behavior, Animal / drug effects Brain / drug effects Clozapine / analogs & derivatives 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

Journal

Nature neuroscience
ISSN: 1546-1726
Titre abrégé: Nat Neurosci
Pays: United States
ID NLM: 9809671

Informations de publication

Date de publication:
09 2020
Historique:
received: 03 12 2019
accepted: 27 05 2020
pubmed: 8 7 2020
medline: 1 12 2020
entrez: 8 7 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41593-020-0661-3 PMID: 32632286
pubmed: 32632286
doi: 10.1038/s41593-020-0661-3
pii: 10.1038/s41593-020-0661-3
doi:

Substances chimiques

Designer Drugs 0
Receptor, Muscarinic M3 0
Receptor, Muscarinic M4 0
11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4)diazepine 1977-07-7
Clozapine J60AR2IKIC

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

1157-1167

Subventions

Organisme : NIMH NIH HHS
ID : U01 MH105892
Pays : United States
Organisme : NIDDK NIH HHS
ID : U24 DK116195
Pays : United States

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Auteurs

Yuji Nagai (Y)

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
ORCID: 0000-0001-7005-0749

Naohisa Miyakawa (N)

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
ORCID: 0000-0001-5057-0333

Hiroyuki Takuwa (H)

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Yukiko Hori (Y)

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Kei Oyama (K)

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Bin Ji (B)

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Manami Takahashi (M)

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Xi-Ping Huang (XP)

Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Samuel T Slocum (ST)

Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
ORCID: 0000-0001-5942-4367

Jeffrey F DiBerto (JF)

Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.

Yan Xiong (Y)

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.

Takuya Urushihata (T)

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Toshiyuki Hirabayashi (T)

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Atsushi Fujimoto (A)

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
ORCID: 0000-0002-1621-2003

Koki Mimura (K)

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Justin G English (JG)

Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
ORCID: 0000-0002-1161-8928

Jing Liu (J)

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.

Ken-Ichi Inoue (KI)

Systems Neuroscience Section, Primate Research Institute, Kyoto University, Inuyama, Japan.
PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan.
ORCID: 0000-0002-5683-5280

Katsushi Kumata (K)

Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Chie Seki (C)

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Maiko Ono (M)

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Masafumi Shimojo (M)

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Ming-Rong Zhang (MR)

Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Yutaka Tomita (Y)

Department of Neurology, Keio University School of Medicine, Tokyo, Japan.

Jin Nakahara (J)

Department of Neurology, Keio University School of Medicine, Tokyo, Japan.

Tetsuya Suhara (T)

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Masahiko Takada (M)

Systems Neuroscience Section, Primate Research Institute, Kyoto University, Inuyama, Japan.

Makoto Higuchi (M)

Department of Functional Brain Imaging, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Jian Jin (J)

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.
ORCID: 0000-0002-2387-3862

Bryan L Roth (BL)

Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. bryan_roth@med.unc.edu.
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.
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.
ORCID: 0000-0002-0561-6520

Takafumi Minamimoto (T)

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.
ORCID: 0000-0003-4305-0174

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Deschloroclozapine, a potent and selective...
questionsmedicales.fr › Comportement et mécanismes comportementaux › Comportement › Comportement animal › Deschloroclozapine, a potent and selective...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Deschloroclozapine, a potent and selective...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérocycliques 3 noyaux › Dibenzazépines › Clozapine › Deschloroclozapine, a potent and selective...
questionsmedicales.fr › Préparations pharmaceutiques › Médicaments de synthèse › Drogues fabriquées clandestinement › Deschloroclozapine, a potent and selective...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Deschloroclozapine, a potent and selective...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Deschloroclozapine, a potent and selective...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Cercopithecidae › Cercopithecinae › Macaca › Macaca fuscata › Deschloroclozapine, a potent and selective...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Cercopithecidae › Cercopithecinae › Macaca › Macaca mulatta › Deschloroclozapine, a potent and selective...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Deschloroclozapine, a potent and selective...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Deschloroclozapine, a potent and selective...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Deschloroclozapine, a potent and selective...
questionsmedicales.fr › Techniques d'investigation › Modèles animaux › Deschloroclozapine, a potent and selective...
questionsmedicales.fr › Cellules › Neurones › Deschloroclozapine, a potent and selective...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs aux neuromédiateurs › Récepteurs cholinergiques › Récepteur muscarinique › Récepteur muscarinique de type M3 › Deschloroclozapine, a potent and selective...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs aux neuromédiateurs › Récepteurs cholinergiques › Récepteur muscarinique › Récepteur muscarinique de type M4 › Deschloroclozapine, a potent and selective...