Deschloroclozapine (DCZ)

Overview

Deschloroclozapine (DCZ) is reported to be a potent, selective and highly brain-penetrable muscarinic hM3Dq and hM4Di DREADD actuator with minimal off-target actions (K_i = 6.3 and 4.2 nM at hM3Dq and hM4Di respectively) and (EC₅₀ values are 0.13 and 0.081 nM at hM3Dq and hM4Di respectively in a BRET-based assay.

It represents a potent, selective, metabolically stable and fast acting DREADD agonist with utility in both mice and non-human primates for a variety of applications.

It shows 100-fold improved affinity and greater agonist potency for hM3Dq and hM4Di compared to Clozapine n-Oxide (CNO) or DREADD agonist 21 (C21) with reduced off-target binding compared with clozapine in vitro.It has lower affinity at D₁, D₂ and 5-HT_2A and 5-HT_2C receptors compared with clozapine.

PET studies demonstrate the compound is rapidly brain penetrable, is apparently selective and doses for DREADD occupancy are 20-fold and 60-fold lower than CNO or DREADD agonist 21 (C21) respectively.

Uses and applications

Systemic delivery of low doses of DCZ (1 or 3 µg/kg) were shown to enhance neuronal activity via hM3Dq in mice and monkeys within minutes.

Intramuscular doses of 100 µg/kg reversibly induced spatial working memory deficits in hM4Di expressing monkeys.

Deschloroclozapine dihydrochloride (water soluble) also available.