IN-VITRO AND IN-VIVO BIOCHEMISTRY OF OLANZAPINE - A NOVEL, ATYPICAL ANTIPSYCHOTIC DRUG

Background: Classical (typical) antipsychotic drugs are in wide use cl inically but some patients do not respond at all to treatment, while i n others, negative symptoms and cognitive deficits fail to respond. Al so, 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 fatal agranulocytosis. Accordingly, we attempted to develop a prototype of a new generation of antipsychotics that is both more efficacious and safe. Our strategy was to create a compound that is not only active in behavioral tests that predict antipsychotic action but also shares the rich, multifacet ed receptor pharmacology of clozapine without its side effects. To thi s end, Eli Lilly and Co, developed olanzapine. In this article we char acterize the in vitro and in vivo receptor pharmacology of olanzapine. Method: We evaluated olanzapine interactions with neuronal receptors using standard assays of radioreceptor binding in vitro and well-estab lished in vivo (functional) assays. Results: Binding studies showed th at olanzapine interacts with key receptors of interest in schizophreni a, having a nanomolar affinity for dopaminergic, seratonergic, alpha(1 )-adrenergic, and muscarinic receptors. In vivo olanzapine is a potent antagonist at DA receptors (DOPAC levels; pergolide-stimulated increa ses in plasma corticosterone) and 5-HT receptors (quipazine-stimulated increases in corticosterone), but is weaker at a-adrenergic and musca rinic receptors, Olanzapine has little or no effect at other receptors , enzymes, or key proteins in neuronal function. Olanzapine has a rece ptor profile that is similar to that of clozapine: it is relatively no nselective at dopamine receptor subtypes and it shows selectivity for mesolimbic and mesocortical over striatal dopamine tracts (electrophys iology; Fos). Conclusion: The binding and functional profile of olanza pine (1) is similar to that of clozapine, (2) indicates that olanzapin e is an atypical antipsychotic drug, and (3) is consistent with clinic al efficacy. If olanzapine: also proves to be safe, then it will have high potential to become a more ideal antipsychotic drug.