The discovery of the benzodiazepine, clozapine 12, in 1959 ushered in a new generation of potentially superior antipsychotic drugs. Clozapine was able to block DA-mediated behavior in animals and exerted antipsychotic effects in humans at doses that did not elicit EPS or produce sustained elevations in serum prolactin levels in humans. The motor symptom profile was sufficiently different from the first-generation antipsychotic drugs such that clozapine was labeled 'atypical' and clozapine became the blueprint for the development of other atypical antipsychotic drugs. Based on this blueprint, close clozapine analogs were developed that include loxapine 45, olanzapine 49, quetiapine 46, and asenapine 50, while the structurally dissimilar benzisoxidil group including risperidone 47, iloperidone 51, and ziprasidone 48, and the phenylindole derivative, sertindole 52.
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