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.
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Data availability
The data that support the findings of this study are available from the corresponding authors upon reasonable request.
Code availability
The code to generate the results and the figures of this study are available from the corresponding authors upon reasonable request.
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Acknowledgements
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’s Strategic Grant (Creative Research) (to N.M.); the Cooperative Research Program at PRI, Kyoto University; the National Bio-Resource Project ‘Japanese Monkeys’ of MEXT, Japan; and U24DK116195, the NIMH Psychoactive Drug Screening Program and the Michael Hooker Distinguished Professorship to B.L.R.
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Conceptualization: T.M. Formal analysis: Y.N., N.M., K.O., K.M. and T.M. Investigation: Y.N., N.M., H.T., Y.H., K.O., B.J., M. Takahashi, X.-P.H., S.T.S., J.F.D., T.U., A.F., J.G.E., K.K., C.S., M.O. and M.S. Resources: B.J., Y.X., J.L., K.-i.I., Y.T., J.N., M. Takada and J.J. Writing (original draft): Y.N., N.M. and T.M. Visualization: Y.N., N.M., H.T., Y.H., K.O., B.J., K.M. and T.M. Supervision: M.-R.Z., T.S., M. Takada, M.H., J.J., B.L.R. and T.M. Project administration: B.L.R. and T.M. Funding acquisition: Y.N., N.M., T.H., K.I., M. Takada, T.S., M.H., J.J., B.L.R., and T.M. Writing (review and editing): all authors.
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Y.N., N.M., B.J., T.S., M.H. and T.M. are named as inventors on a patent application (PCT/JP2019/024834; status: patent pending) claiming subject matter related to the results described in this paper. The remaining authors declare no competing interests.
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Nagai, Y., Miyakawa, N., Takuwa, H. et al. Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys. Nat Neurosci 23, 1157–1167 (2020). https://doi.org/10.1038/s41593-020-0661-3
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DOI: https://doi.org/10.1038/s41593-020-0661-3
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