RRC ID 64862
著者 Nagai Y, Miyakawa N, Takuwa H, Hori Y, Oyama K, Ji B, Takahashi M, Huang XP, Slocum ST, DiBerto JF, Xiong Y, Urushihata T, Hirabayashi T, Fujimoto A, Mimura K, English JG, Liu J, Inoue KI, Kumata K, Seki C, Ono M, Shimojo M, Zhang MR, Tomita Y, Nakahara J, Suhara T, Takada M, Higuchi M, Jin J, Roth BL, Minamimoto T.
タイトル Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys.
ジャーナル Nat Neurosci
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.
巻・号 23(9)
ページ 1157-1167
公開日 2020-9-1
DOI 10.1038/s41593-020-0661-3
PII 10.1038/s41593-020-0661-3
PMID 32632286
MeSH 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
IF 20.071
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