@article{7c6a337e30ce482aa0d8733fd51d450a,
title = "Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys",
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.",
author = "Yuji Nagai and Naohisa Miyakawa and Hiroyuki Takuwa and Yukiko Hori and Kei Oyama and Bin Ji and Manami Takahashi and Huang, {Xi Ping} and Slocum, {Samuel T.} and DiBerto, {Jeffrey F.} and Yan Xiong and Takuya Urushihata and Toshiyuki Hirabayashi and Atsushi Fujimoto and Koki Mimura and English, {Justin G.} and Jing Liu and Inoue, {Ken ichi} and Katsushi Kumata and Chie Seki and Maiko Ono and Masafumi Shimojo and Zhang, {Ming Rong} and Yutaka Tomita and Jin Nakahara and Tetsuya Suhara and Masahiko Takada and Makoto Higuchi and Jian Jin and Roth, {Bryan L.} and Takafumi Minamimoto",
note = "Funding Information: We thank R. Suma, J. Kamei, R. Yamaguchi, Y. Matsuda, Y. Sugii, A. Maruyama, T. Okauchi, T. Kokufuta, Y. Iwasawa, T. Watanabe, A. Tanizawa, S. Shibata, N. Nitta, Y. Ozawa, M. Fujiwara, M. Nakano, T. Minamihisamatsu, S. Uchida and S. Sasaki for their technical assistance. We also thank S. Hiura for 3D printing of the grids. This study was supported by the following grants and organizations: MEXT/JSPS KAKENHI grant numbers JP15H05917, JP15K12772 and JP18H04037 (to T.M.), JP16H02454 (to M. Takada), JP19K08138 (to Y.N.), and JP18H05018, JP19K07811 and JP20H04596 (to N.M.); AMED grant numbers JP20dm0107146 (to T.M.), JP19dm0207003 (to M. Takada), JP20dm0107094 and JP18dm0207007 (to T.S.), JP20dm0307021 (to K.-i.I.), JP20dm0307007 (to T.H.), and JP20dm0207072 (to M.H.); JST PRESTO grant number JPMJPR1683 (to K.-i.I.); QST President{\textquoteright}s Strategic Grant (Creative Research) (to N.M.); the Cooperative Research Program at PRI, Kyoto University; the National Bio-Resource Project {\textquoteleft}Japanese Monkeys{\textquoteright} of MEXT, Japan; and U24DK116195, the NIMH Psychoactive Drug Screening Program and the Michael Hooker Distinguished Professorship to B.L.R. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2020",
month = sep,
day = "1",
doi = "10.1038/s41593-020-0661-3",
language = "English",
volume = "23",
pages = "1157--1167",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "9",
}