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In Vitro and In Vivo Biochemistry of Olanzapine: A Novel, Atypical Antipsychotic Drug

Frank P. Bymaster, M.S., Kurt Rasmussen, Ph.D., David O. Calligaro, Ph.D., David L. Nelson, Ph.D., Neil W. DeLapp, Ph.D., David T. Wong, Ph.D., and Nicholas A. Moore, Ph.D.

Published: June 1, 1997

Article Abstract

Background: Classical (typical) antipsychotic drugs are in wide use clinically, but some patientsdo not respond at all to treatment, while in others, negative symptoms and cognitive deficits fail torespond. Also, these drugs often cause serious motor disturbances. Clozapine, an atypical antipsychotic,appears to correct many of these deficiencies, but has a significant incidence of potentially fatalagranulocytosis. Accordingly, we attempted to develop a prototype of a new generation of antipsychoticsthat is both more efficacious and safe. Our strategy was to create a compound that is not only activein behavioral tests that predict antipsychotic action but also shares the rich, multifaceted receptor pharmacologyof clozapine without its side effects. To this end, Eli Lilly and Co. developed olanzapine. Inthis article we characterize the in vitro and in vivo receptor pharmacology of olanzapine. Method: Weevaluated olanzapine interactions with neuronal receptors using standard assays of radioreceptor bindingin vitro and well-established in vivo (functional) assays. Results: Binding studies showed thatolanzapine interacts with key receptors of interest in schizophrenia, having a nanomolar affinity fordopaminergic, serotonergic, α1-adrenergic, and muscarinic receptors. In vivo olanzapine is a potentantagonist at DA receptors (DOPAC levels; pergolide-stimulated increases in plasma corticosterone)and 5-HT receptors (quipazine-stimulated increases in corticosterone), but is weaker at α-adrenergicand muscarinic receptors. Olanzapine has little or no effect at other receptors, enzymes, or key proteinsin neuronal function. Olanzapine has a receptor profile that is similar to that of clozapine: it is relativelynonselective at dopamine receptor subtypes and it shows selectivity for mesolimbic and mesocorticalover striatal dopamine tracts (electrophysiology; Fos). Conclusion: The binding and functionalprofile of olanzapine (1) is similar to that of clozapine, (2) indicates that olanzapine is anatypical antipsychotic drug, and (3) is consistent with clinical efficacy. If olanzapine also proves to besafe, then it will have high potential to become a more ideal antipsychotic drug.

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Volume: 58

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