CLOZAPINE N-OXIDE

Description

Clozapine-N-oxide (34233-69-7) is a clozapine?metabolite1?which is pharmacologically inert2. Agonist at human muscarinic designer receptors known as DREADDs, (designer receptors exclusively activated by designer drug).2?May be used to control grafted human pluripotent stem cell-derived neurons engineered to express DREADDs.3,4??Numerous other applications.5,6

Chemical Properties

Yellow Solid

Uses

Clozapine N-oxide has been used:

• for the activation of human M4 muscarinic (hM4Di) in primary motor cortex
• for inducing in vivo chemogenetic manipulation and impairing locomotor activity in Th-cre transgenic mice
• in behavioral testing in mice and for stimulating (HEK293) cells

Uses

A 5-HT2 antagonist. A major metabolite of clozapine that can be monitored by HPLC. Possesses little or no activity towards serotonin receptors

Definition

ChEBI: Clozapine N-oxide is a dibenzodiazepine.

General Description

Clozapine N-oxide (CNO), inactive from of clozapine drug, activates G-protein-coupled receptors (GPCRs). CNO serves as a synthetic ligand for engineered human muscarinic receptor. It elicits clozapine-like effects upon metabolic conversion. Clozapine conversion to CNO favors its passage through blood-brain barrier.

Biochem/physiol Actions

5-HT2 serotonin receptor antagonist; major metabolite of clopazine that can be monitored by HPLC.

storage

Room temperature (desiccate)

References

1) Eiermann?et al.?(1997),?The involvement of CYP1A2 and CYP3A4 in the metabolism of clozapine; Br. J. Clin. Pharmacol.,?44?439 2) Armbruster?et al.?(2007),?Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand; Proc. Natl. Acad. Sci. USA,?104?5163 3) Chen?et al.?(2016),?Chemical Control of Grafted Human PSC-Derived Neurons in a Mouse Model of Parkinson’s Disease; Cell Stem Cell,?18?817 4) Vazey and Aston-Jones (2014),?Designer receptors: therapeutic adjuncts to cell replacement therapy in Parkinson’s disease: J. Clin. Invest.,?124?2858 5) Gomez?et al.?(2017)?Chemogenetics revealed: DREADD occupancy and activation via converted clozapine; Science?357?503 6) Marcinkiewcz?et al. (2016)?Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala; Nature?537?97