The Clozapine Hypothesis

Clozapine 12 is the prototypic atypical antipsychotic, which has broad spectrum efficacy in schizophrenia, being efficacious in the treatment of refractory schizophrenics, with potential efficacy in treating cognitive deficits and having a lower extrapyramidal side effects (EPSs) liability.20'21 These positive attributes are however limited by a high incidence of potentially fatal agranulocytosis that requires continuous monitoring in the clinical situation.

Based on the favorable therapeutic profile of clozapine, there has been an intense effort in the pharmaceutical industry over the past 30 years to identify clozapine-like new chemical entities (NCEs) that have the efficacy attributes of clozapine without the agranulocyotosis. This has led to a slew of second-generation atypical antipsychotics, discussed in detail below, none of which has achieved the efficacy seen with clozapine. This search has been largely based on the receptor binding profile of clozapine, in itself a challenge since, with each newly identified CNS receptor, the subsequent evaluation of clozapine tends to result in yet another potential pharmacological property being added to the profile of the compound.22 Thus the chemist is challenged to synthesize compounds active at what are thought to be the primary molecular targets of clozapine, the DA D2 and 5HT2 receptors, anticipating that the binding profile will result in an approximation of the intrinsic activity and receptor ratios of clozapine at both the primary and the as-yet unknown ancillary targets, that lead to the unique antipsychotic profile of this molecule. A facile approach to the discovery of new antipsychotics has been to replicate the molecular properties of clozapine on a more or less trial-and-error basis. More recently, the N-desmethyl metabolite of clozapine 13, which functions as a muscarinic receptor agonist, has been proposed as the key to understanding the unique properties of the parent drug.23

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