Structure and toxicity of clozapine and olanzapine on agranulocytosis

The structure and toxicity relationship of the dibenzo-1,4-diazepine derivatives has been investigated using quantum chemical calculations at the density functional theory level/B3LYP with the 6-311G(d,p) basis sets by electron or hydrogen transfer calculations as model for the reaction prediction between the derivatives and the free radical species on agranulocytosis. Our results show that the abstraction of an electron or hydrogen from the amino group of the olanzapine is more favored than clozapine. The spin density calculations performed for the radicals formed clarify that olanzapine is more stable than clozapine. These results support that the highest toxicity of the 1,4-dibenzodiazepine compounds on agranulocytosis can be related with a high reactivity of diazepine ring in agreement to experimental results. The toxicity of dibenzo-1,4-diazepine derivatives is more related to hydrogen than electron transfers.