| Literature DB >> 32632286 |
Yuji Nagai1, Naohisa Miyakawa1, Hiroyuki Takuwa1, Yukiko Hori1, Kei Oyama1, Bin Ji1, Manami Takahashi1, Xi-Ping Huang2,3, Samuel T Slocum2, Jeffrey F DiBerto2, Yan Xiong4, Takuya Urushihata1, Toshiyuki Hirabayashi1, Atsushi Fujimoto1, Koki Mimura1, Justin G English2, Jing Liu4, Ken-Ichi Inoue5,6, Katsushi Kumata7, Chie Seki1, Maiko Ono1, Masafumi Shimojo1, Ming-Rong Zhang7, Yutaka Tomita8, Jin Nakahara8, Tetsuya Suhara1, Masahiko Takada5, Makoto Higuchi1, Jian Jin4, Bryan L Roth9,10,11, Takafumi Minamimoto12.
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.Entities:
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Year: 2020 PMID： 32632286 DOI： 10.1038/s41593-020-0661-3
Source DB: PubMed Journal: Nat Neurosci ISSN： 1097-6256 Impact factor: 24.884