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

The chemogenetic technology, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), affords reversible and remote control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, the sluggish kinetics, metabolic liabilities, and potential for off-target effects of CNO represent areas for improvement. Here we provide a new agonist deschloroclozapine (DCZ), which displays high affinity and selectivity 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/kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injection of DCZ (100 µg/kg) reversibly induced behavioral deficits in hM4Di-expressing monkeys. 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.