Deschloroclozapine (DCZ) is a high-affinity and selective agonist for muscarinic-based DREADDs, shows nanomolar affinity for [3H]QNB-labeled hM3Dq and hM4Di with Ki of 6.3 and 4.2 nM, respectively.
DCZ shows negligible affinities for a large number of GPCRs, ion channels and transporters (Ki values of >100 nM) and relatively low affinities for a few endogenous receptors, including muscarinic acetylcholine (hM1Ki=83 nM, hM5Ki =55 nM) and serotonin receptors (5-HT2AKi = 87 nM).
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.