Clozapine discovery

Examples abound regarding the role of serendipity in the discovery of new therapeutic approaches, which on closer examination usually turned out to be the result of clinicians paying attention to unexpected clinical effects rather than discounting them. For example, lithium was tried first for hypertension, chlorpro-mazine was initially developed as an anesthetic, and imipramine was originally regarded as an antihistamine and an antipsychotic agent. Without astute clinical observations, these drugs would not have found their niche, nor would clozapine have been revived for the benefit of millions of the most difficult to treat schizophrenic patients. Other examples include the expanded indications of newer... 

Detailed studies of the binding of H-labelled haloperidol to neuronal membranes showed that there was a much better correlation between the therapeutic potency of a neuroleptic and its ability to displace this ligand from the nerve membrane. This led to the discovery of two types of dopamine receptor that are both linked to adenylate cyclase but whereas the Di receptor is positively linked to the cyclase, the D2 receptor is negatively linked. It was also shown that the receptor is approximately 15 times more sensitive to the action of dopamine than the D2 receptor conversely, the receptor has a low affinity for the butyrophenone and atypical neuroleptics such as clozapine, whereas the D2 receptor appears to have a high affinity for most therapeutically active neuroleptics. 

An important breakthrough in the development of novel neuroleptics arose over 25 years ago with the discovery of the dibenzazepine neuroleptic clozapine. This neuroleptic was novel because it attenuated both the positive and negative symptoms of schizophrenia without causing extrapyramidal side effects or elevating serum prolactin concentrations, effects which characterize most typical neuroleptics such as chlorpromazine and haloperidol. 

The synthesis and discovery of the antipsychotic effects of the piperazinyl-dibenzoazepine, clozapine (Fig. 13.1) and its launch in 1972 was an important turning point in the drug treatment of schizophrenia [1-3]. Clozapine was called an atypical antipsychotic as it did not produce side effects characteristic for compounds of the chlorpromazine- or haloperidol-type (i.e., extrapyramidal symptoms) either in animal models or in the clinic. Its use, however, became very limited when it was recognized that clozapine might cause a severe, and sometimes fatal, form of agranulocytosis. 

The discovery of the atypical antipsychotic clozapine opened a new era and set new standards in the drug treatment of schizophrenia. Modifications of the diben-zoazepine structure in clozapine resulted in olanzapine and quetiapine, which are among the most frequently used antipsychotic drugs. From a chemical viewpoint, clozapine, olanzapine and quetiapine can be considered as structural analogues. Although they share some common features in their molecular mechanism of action, the three compounds show significant differences in their clinical efficacy and adverse event profile. 

Unfortunately, potentially fatal agranulocytosis appears in 1-2% of patients treated with clozapine (7). This necessitates frequent blood monitoring, which can be inconvenient and expensive. Furthermore, despite its low potential for causing EPS and TD, clozapine causes other, dose-related side effects that can limit its effectiveness in some patients. The precise pharmacological actions of clozapine responsible for its clinical effectiveness are still being debated. Attempts to duplicate elements cf its complex pharmacological profile have led to the discovery of several new atypical antipsychotic drugs that have been approved in the United States for the treatment of schizophrenia. 

Clozapine has had a checkered history from its initial discovery in the late 1960s by German and Austrian clinicians (283) to its redis-covay in the United States in the 1980s. It was synthesized initially as part of an effort to... 

With the discovery of atypical agents such as clozapine and thioridazine, companies began... 

HT2A Antagonists. As described in Section 8.1.4, the discovery that clozapine... 

Malhotra AK, Athanasiou M, Reed CR, et al. Discovery of genetic markers associated with clozapine induced agranulocytosis. Am JMedGenetBNeuropsychiatr Genet 2005 138b 22. 

The discovery that D and receptors are preferentially expressed in limbic areas has led to efforts to identify selective inhibitors for these receptors that might have antipsychotic efficacy and low risk of extrapyramidal effects. Clozapine has modest selectivity for D receptors over other DA receptor types. D receptors, preferentially localized in cortical and limbic brain regions in relatively low abundance, are upregulated after repeated administration of most typical and atypical antipsychotic drugs. These receptors may contribute to clinical antipsychotic actions, but agents that are selective or mixed DyS antagonists have not proved effective in the treat-... 

---