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

• Published in: Nature neuroscience Vol. 23; no. 9; pp. 1157 - 1167
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-09-2020; Nature Publishing Group
• Subjects: 13; 38/44; 59/78; 631/1647; 631/378; Acetylcholine receptors (muscarinic); Actuators; Agonists; Animal Genetics and Genomics; Animals; Behavior, Animal - drug effects; Behavioral Sciences; Biochemical genetics; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Brain - drug effects; Clinical neuropsychology; Clozapine; Clozapine - analogs & derivatives; Clozapine - pharmacology; Designer Drugs - pharmacology; Genetic Techniques; Humans; Liabilities; Macaca fuscata; Macaca mulatta; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Animal; Monkeys; Neurobiology; Neurons - drug effects; Neurosciences; Positron emission; Positron emission tomography; Prefrontal cortex; Primates; Receptor, Muscarinic M3 - metabolism; Receptor, Muscarinic M4 - metabolism; Remote control; Short term memory; Spatial memory; technical-report; Testing; Tomography; Japan
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-020-0661-3

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.
Deschloroclozapine (DCZ) is a broadly useful chemogenetic agonist for studies using nonhuman primates and mice. DCZ rapidly and reversibly activates DREADDs, and its binding can be visualized noninvasively by positron emission tomography.