Synthesis of Rigid Analogs of Antipsychotic Clozapine

This proposal is for the synthesis and testing of rigid analogs of the antipsychotic drug clozapineclozapine does not cause extrapyramidal and endocrine side effects that are typical of antipsychoticagranulocytosis in 1-2% of schizophrenics who take the drug. Because of this, there is a need for aantipsychotic drug that does not cause this potentially fatal side effect. Based on molecular modeliidentified the structural features that distinguish clozapine from other antipsychotic drugs. This wcompounds that share those structural features in a rigid structure. These compounds were energy minMM2-87 program and the resultant structures were superimposed onto a crystal structure of clozapinesquares sense to determine which compounds were the best fit to clozapine and to prioritize the rigisynthesis. The synthesized compounds will be screened for affinity at dopamine D2, D3, and D4 receptatypical profile of clozapine appears to be due to its D4 selectivity relative to D2 receptors. Thethis proposal is to develop a clozapine-like antipsychotic drug that does not cause agranulocytosis.