|Description||Potent, selective and metabolically stable hM3Dq and hM4Di muscarinic DREADD actuator.|
|Biological description|| |
Deschloroclozapine (DCZ) is reported to be a potent, selective and highly brain-penetrable muscarinic hM3Dq and hM4Di DREADD actuator with minimal off-target actions (Ki = 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-HT2A and 5-HT2C 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.
Solubility & Handling
|Storage instructions||Room temperature|
|Solubility overview||Soluble in DMSO (100 mM), and in ethanol (50 mM with warming)|
|Important||This product is for RESEARCH USE ONLY and is not intended for therapeutic or diagnostic use. Not for human or veterinary use|
References for Deschloroclozapine (DCZ)
Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeysNagai et al (2020) Nature Neuroscience : 1157-1167
Chemogenetic actuator drugs impair prefrontal cortex-dependent working memory in rhesus monkeysUpright and Baxter (2019) bioRxiv : https://doi.org/10.1101/864140
Binding of 5H-dibenzo[b,e][1,4]diazepine and chiral 5H-dibenzo[a,d]cycloheptene analogues of clozapine to dopamine and serotonin receptors.Phillips et al (1994) J Med Chem 37(17) : 2686-96