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

Yuji Nagai; Naohisa Miyakawa; Hiroyuki Takuwa; Yukiko Hori; Kei Oyama; Bin Ji; Manami Takahashi; Xi‐Ping Huang; Samuel T. Slocum; Jeffrey F. DiBerto; Yan Xiong; Takuya Urushihata; Toshiyuki Hirabayashi; Atsushi Fujimoto; Koki Mimura; Justin G. English; Jing Liu; Ken‐ichi Inoue; Katsushi Kumata; Chie Seki; Maiko Ono; Masafumi Shimojo; Ming-Rong Zhang; 裕 冨田; Jin Nakahara; Tetsuya Suhara; Masahiko Takada; Makoto Higuchi; Jian Jun Jin; Bryan L. Roth

doi:10.1038/s41593-020-0661-3

NeuroscienceNature NeuroscienceJul 6, 2020

Peer-reviewed journal article

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

Yuji Nagai iD, Naohisa Miyakawa iD, Hiroyuki Takuwa iD, Yukiko Hori iD, Kei Oyama iD, Bin Ji iD, Manami Takahashi iD, Xi‐Ping Huang iD, Samuel T. Slocum iD, Jeffrey F. DiBerto iD, Yan Xiong iD, Takuya Urushihata iD, Toshiyuki Hirabayashi iD, Atsushi Fujimoto iD, Koki Mimura iD, Justin G. English iD, Jing Liu iD, Ken‐ichi Inoue iD, Katsushi Kumata, Chie Seki iD, Maiko Ono iD, Masafumi Shimojo iD, Ming-Rong Zhang iD, 裕冨田, Jin Nakahara iD, , Takafumi Minamimoto iD

Abstract

The chemogenetic technology Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) affords 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 g/kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 g/kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents the most potent, selective, metabolically stable and fast-acting DREADD agonist reported with utility in both mice and non-human primates for a variety of applications.

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