Modification of olanzapine to control the metabolic disorders associated with schizophrenia therapy

Schizophrenia is a complex mental disorder which is accompanied with various positive and/or negative symptoms. Among the prescribed antipsychcotics for treatment of schizophrenia, atypical antipsychotics including olanzapine (zyprexa) have been used as the first line of therapeutic programs. The unique therapeutic feature of olanzapine associated with low incidence of EPS (Extrapyramidal Symptoms) has been recognized to be correlated with its broad neuronal receptor binding benefits including binding to the D-2, D-4, 5-HT2A and 5-HT2C as well as D-1, α-1, α-2 and M-1 receptors. However, the H-1 antagonist propensity of olanzapine, and that of other atypical antipsychotics, induces excessive weight gain, type II diabetes and obesity-related conditions such as cardiovascular disease. This dissertation focused on structural modification of olanzapine to a new antipsychotic with H-1 agonist activity or to a new drug with lower affinity for the H-1 receptor. Computer-aided drug design techniques were utilized, centering on the development of a H-1 agonist pharmacophore based on the available published ligands. The resulting pharmacophore proposed three modifications to the structure of olanzapine including: 1) replacement of the methyl group with an ethyl group at position C-2; 2) substitution of a hydroxymethyl group at position C-3; and 3) removal of the distal nitrogen from position N-4ʹ (Table 3.1, page 41). The diazepine compounds 99 and 101 were synthesised successfully representing a single modification at position C-2 and N-4ʹ, respectively. Substitution of a hydroxymethyl group at position C-3 of olanzapine was not successful; however, the formamide compound 145 with a formamide group at position N-10 was accidentally obtained (Scheme 3.21, page 69). The diazepine derivatives 99, 101, 145 and also 102 with two modifications at positions C-2 and N-4ʹ were subjected to pharmacological evaluation. In the scope of this project competitive binding assays were attempted. The obtained IC50 value from these experiments revealed that the diazepine compound 99 (IC50: 9.78 x 10-7 M) had significant reduced binding affinity compared to that of olanzapine (IC50: 2.08 x 10-9 M) for the H-1 receptor. This result was related to the effect of the ethyl group at position C-2. The formamide compound 145 (IC50: 3.70 x 10-8 M) also had reduced binding affinity of olanzapine to the H-1 receptor; however, due to the poor dose-response behavior of the diazepine compound 101 (IC50: 0.5 M) the effect of removing the distal nitrogen from position N-4ʹ is questionable and needs further investigations