title: In vitro and in vivo biochemistry of olanzapine: a novel, atypical antipsychotic drug.
abstract: BACKGROUND
  Classical (typical) antipsychotic drugs are in wide use clinically, but some patients do not respond at all to treatment, while in others, negative symptoms and cognitive deficits fail to respond. 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 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, multifaceted receptor pharmacology of clozapine without its side effects. To this end, Eli Lilly and Co. developed olanzapine. In this article we characterize the in vitro and in vivo receptor pharmacology of olanzapine.
  
  
  METHODS
  We evaluated olanzapine interactions with neuronal receptors using standard assays of radioreceptor binding in vitro and well-established in vivo (functional) assays.
  
  
  RESULTS
  Binding studies showed that olanzapine interacts with key receptors of interest in schizophrenia, having a nanomolar affinity for dopaminergic, serotonergic, alpha 1-adrenergic, and muscarinic receptors. In vivo olanzapine is a potent antagonist at DA receptors (DOPAC levels; pergolide-stimulated increases in plasma corticosterone) and 5-HT receptors (quipazine-stimulated increases in corticosterone), but is weaker at alpha-adrenergic and muscarinic receptors. Olanzapine has little or no effect at other receptors, enzymes, or key proteins in neuronal function. Olanzapine has a receptor profile that is similar to that of clozapine: it is relatively nonselective at dopamine receptor subtypes and it shows selectivity for mesolimbic and mesocortical over striatal dopamine tracts (electrophysiology; Fos).
  
  
  CONCLUSIONS
  The binding and functional profile of olanzapine (1) is similar to that of clozapine, (2) indicates that olanzapine is an atypical antipsychotic drug, and (3) is consistent with clinical efficacy. If olanzapine also proves to be safe, then it will have high potential to become a more ideal antipsychotic drug.
authors.affiliation: Lilly Neurosciences Research, Eli Lilly and Company Indianpolis 46285, USA.
authors.forename: F P
authors.initials: FP
authors.lastname: Bymaster
authors.forename: K
authors.initials: K
authors.lastname: Rasmussen
authors.forename: D O
authors.initials: DO
authors.lastname: Calligaro
authors.forename: D L
authors.initials: DL
authors.lastname: Nelson
authors.forename: N W
authors.initials: NW
authors.lastname: DeLapp
authors.forename: D T
authors.initials: DT
authors.lastname: Wong
authors.forename: N A
authors.initials: NA
authors.lastname: Moore
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines; D002626:Chemistry, Pharmaceutical; D006224:Cricetinae; D015195:Drug Design; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D000077152:Olanzapine; D010601:Pharmacology, Clinical; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011941:Receptors, Adrenergic / Q000187:drug effects; D011950:Receptors, Cholinergic / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000187:drug effects; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D011941:Receptors, Adrenergic; D011950:Receptors, Cholinergic; D011976:Receptors, Muscarinic; D017981:Receptors, Neurotransmitter; D011985:Receptors, Serotonin; D001569:Benzodiazepines; D010890:Pirenzepine; D000077152:Olanzapine