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Clozapine, a Fast-Off-D2 Antipsychotic

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Departments of Pharmacology and Psychiatry, University of Toronto, 260 Heath Street West, Unit 605, Toronto, Ontario, Canada M5P 3L6
Cite this: ACS Chem. Neurosci. 2014, 5, 1, 24–29
Publication Date (Web):November 12, 2013
https://doi.org/10.1021/cn400189s
Copyright © 2013 American Chemical Society

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    Abstract

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    Ever since clozapine was first synthesized and tested, it showed the unique property of having antipsychotic action but no Parkinson-like motor side effects. The antipsychotic basis of clozapine is to transiently occupy dopamine D2 receptors in the human striatum, in contrast to haloperidol and chlorpromazine, which have a prolonged occupation of D2 receptors. The chemical structure of clozapine facilitates a relatively rapid dissociation from D2 receptors. After short-term occupation of D2 receptors, peak neural activity raises synaptic dopamine, which then displaces clozapine. While clozapine also occupies other types of receptors, they may not have a significant role in preventing parkinsonism. Clozapine’s transient occupation of D2 receptors permits patients to move easily and comfortably.

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