Synthesis and pharmacological evaluation of olanzapine analogues as potential antipsychotics

Schizophrenia is a debilitating mental disorder characterised by delusions, hallucinations, lack of emotion and motivation, as well as cognitive deficits. Imbalance in the dopaminergic neuronal system has been closely linked with symptoms of schizophrenia. Treatment is undertaken with antipsychotics, which are designed to address the dopaminergic imbalance, through action at dopaminergic and/or serotonergic receptors. The work in this thesis was designed to investigate analogues of olanzapine, a currently prescribed antipsychotic, with the aim of developing agents with potent dopamine D₂ and serotonin 5-HT₂ᴀ receptor affinity. The analogues were designed to incorporate a distal aryl system, linked to olanzapine by an appropriate spacer, depicted in Figure A. Figure A. General structure of proposed analogues of olanzapine The nature of the linker and the distal aryl system were varied, with inspiration drawn from structures present in other commercially available antipsychotics. Analogues were initially assessed in vitro, with a number of them shown to be high affinity ligands for the D₂ and 5-HT₂ᴀ receptors. The most promising analogues were further assessed in an in vivo model, inhibition of apomorphine-induced climbing in mice, predictive of CNS antidopaminergic activity. Analogues highlighted in Figure B were identified as promising leads, showing improved potency compared to olanzapine both in vitro and in vivo. Figure B. Selected analogues produced in this thesis with their pharmacological profiles (Ki, and ED50) compared to olanzapine