DOI: 10.1101/477513Nov 24, 2018Paper

Olanzapine: a full and potent agonist at the hM4D(Gi) DREADD amenable to clinical translation of chemogenetics

BioRxiv : the Preprint Server for Biology
Mikail WestonAndreas Lieb

Abstract

Designer receptors exclusively activated by designer drugs (DREADDs) derived from muscarinic receptors are a powerful tool to test causality in basic neuroscience, but are also potentially amenable to clinical translation. A major obstacle is however that the widely-used agonist clozapine-N-oxide undergoes conversion to clozapine, which penetrates the blood-brain barrier but has an unfavorable side effect profile. Perlapine has been reported to activate DREADDs at nanomolar concentrations, but is not approved for use in humans by the Food and Drug Administration or European Medicines Agency, limiting its translational potential. Here we report that the atypical antipsychotic drug olanzapine, widely available in various formulations, is a full and potent agonist of the human muscarinic-receptor M4-based DREADD, facilitating clinical translation of chemogenetics to treat CNS diseases.

Related Concepts

Brain
CNS Disorder
Clozapine
Designer Drugs
Muscarinic Acetylcholine Receptor
Antipsychotic Agents
Perlapine
GTP-Binding Protein alpha Subunit, Gi
Olanzapine
Agonists

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