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

Nagai, Y.; Miyakawa, N.; Takuwa, H.; Hori, Y.; Oyama, K.; Ji, B.; Takahashi, M.; Huang, X.-P.; Slocum, S.; DiBerto, J. F.; Xiong, Y.; Urushihata, T.; Hirabayashi, T.; Fujimoto, A.; Mimura, K.; English, J. G.; Liu, J.; Inoue, K.-i.; Kumata, K.; Seki, C.; Ono, M.; Shimojo, M.; Zhang, M.-R.; Tomita, Y.; Suhara, T.; Takada, M.; Higuchi, M.; Jin, J.; Roth, B. L.; Minamimoto, T.

doi:10.1101/854513

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bioRxiv · 10.1101/854513

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

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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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Nagai, Y., Miyakawa, N., Takuwa, H., Hori, Y., Oyama, K., Ji, B., Takahashi, M., Huang, X.-P., Slocum, S., DiBerto, J. F., Xiong, Y., Urushihata, T., Hirabayashi, T., Fujimoto, A., Mimura, K., English, J. G., Liu, J., Inoue, K.-i., Kumata, K., Seki, C., Ono, M., Shimojo, M., Zhang, M.-R., Tomita, Y., Suhara, T., Takada, M., Higuchi, M., Jin, J., Roth, B. L., Minamimoto, T.. 2019-12-03. Deschloroclozapine: a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys. https://doi.org/10.1101/854513

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