This proposal is for the synthesis and testing of rigid analogs of the antipsychotic drug clozapine. While clozapine does not cause extrapyramidal and endocrine side effects that are typical of antipsychotic drugs, it causes agranulocytosis in 1-2% of schizophrenics who take the drug. Because of this, there is a need for a clozapine-like antipsychotic drug that does not cause this potentially fatal side effect. Based on molecular modeling studies, the PI has identified the structural features that distinguish clozapine from other antipsychotic drugs. This was used to design compounds that share those structural features in a rigid structure. These compounds were energy minimized with the MM2-87 program and the resultant structures were superimposed onto a crystal structure of clozapine in the least squares sense to determine which compounds were the best fit to clozapine and to prioritize the rigid analogs for synthesis. The synthesized compounds will be screened for affinity at dopamine D2, D3, and D4 receptors since the atypical profile of clozapine appears to be due to its D4 selectivity relative to D2 receptors. The long term objective of this proposal is to develop a clozapine-like antipsychotic drug that does not cause agranulocytosis.
The development of a clozapine-like drug that does not cause agranulocytosis would be a valuable treatment for schizophrenia. Such a compound would be cheaper that clozapine since it would not require weekly blood exams and could be used for long term maintenance therapy of schizophrenics to reduce the incidence of expensive hospitalizations.
