Degree Name

Doctor of Philosophy


School of Health Sciences


Design, Synthesis and Pharmacological Evaluation of Novel Antipsychotic Drugs Based on Olanzapine that Display Reduced Weight Gain and Metabolic Side Effects”Somayeh Jafari University of Wollongong, 2012

Olanzapine (Olz) is an effective antipsychotic drug for treating severe psychotic disorders, including schizophrenia and bipolar disorders. However, Olz administration is associated with severe weight gain, type II diabetes mellitus, and cardiovascular diseases. Clinical efficiency of Olz has been reported to be linked with its favourable serotoninergic 2A and dopamine 2 (5HT2A/D2) receptor binding affinity ratios, while the blockade of the histamine 1 (H1) receptor is the most likely mechanism for Olz-induced weight gain. Thus, a novel antipsychotic drug with a similar 5HT2A/D2 receptor binding profile as Olz but with reduced affinity for H1 receptor would be an invaluable breakthrough in schizophrenia therapy.

This dissertation focused on the development of novel Olz derivatives with a lower in vitro binding affinity for the H1 receptors, but with a similar 5HT2A/D2 receptor binding affinity ratio to the one observed for Olz. Two new derivatives of Olz, (2-ethyl-4-(4'-methylpiperazin-1'-yl) -10Hbenzo[b]thieno[2,3-e][1,4]diazepine (OlzEt) and (2-ethyl-4-(4'-methyl-1',4'-diazepan-1'-yl)-10H-benzo[b]thieno[2,3-e] [1,4]diazepine (OlzHomo), were synthesized and the affinities of these compounds for the brain 5HT2A, D2, and H1 receptors were evaluated. OlzEt represents a potential antipsychotic agent characterized by a highly favourable binding profile at 5HT2A (Ki: 3.70 ± 0.74 nM) and D2 (Ki: 54.51 ± 12.12 nM) receptors, similar to Olz (Ki: 4.22 ± 0.77 nM and Ki: 67.72± 9.21 nM, respectively), as well as lower affinity for H1 receptors (Ki (Olz): 0.13 ± 0.02 nM and Ki (OlzEt): 1.95 ± 0.33 nM). OlzHomo presented lower binding affinities to all the aforementioned receptors (Ki: 81.20 ± 2.43 nM, Ki: 791.08 ± 83.19 nM, and Ki: 13.63 ± 2.68 nM, respectively). Taking into account that OlzHomo possessed a favourable pKi ratio 5HT2A/D2 similar to the measured value of Olz (ratio value = 1.17) and that the D2 affinity of thienobenzodiazepine OlzHomo is still comparable with that value of the high potent antipsychotics, it was postulated that both compounds OlzHomo and OlzEt may present therapeutic effectiveness for treating schizophrenia. In addition, these compounds present a lower affinity for H1 receptors, which may have reduced effects on weight gain and metabolic disorders than those reported with Olz.

Further, this study aimed to compare the liability of Olz, OlzEt and OlzHomo to induce weight gain in female rats in detail, incorporating indicate of weight gain, food and water intake, visceral fat deposition and measures of plasma hormones related to body weight maintenance (i.e., insulin, leptin, and adiponectin). The present findings confirmed the obesogenic effect of Olz administration, coupled with down-regulation of the H1 receptors in the hypothalamus. OlzEt and OlzHomo, though, turned up as promising antipsychotic compounds that did not induce enhancing effects on body weight and food intake or detrimental consequences on fat deposition and metabolism. In addition, a PCP-treated rat model was employed to examine the prevention of PCP induced hyperlocomotor activity relevant for the treatment of schizophrenia. Behavioural assessment in the open-field test predicted the similar effectiveness of OlzEt to Olz for blocking PCP-induced hyperactivities. The study also showed the long lasting down-regulation of D2 and 5HT2A receptors induced by sub-chronic Olz and OlzEt treatment, which may play a part in blocking PCP-induced behaviours. A lower potency of OlzHomo to inhibit PCP-induced behaviours was observed, which could also be explained by its lower affinity for the brain D2 and 5HT2A receptors compared to that of Olz and OlzEt. Therefore, the therapeutic effectiveness of an OlzHomo regime may be delivered at higher dose than that of Olz and OlzEt treatment.

The present findings appear to have reasonable predictive validity for different aspects of Olz-induced weight gain/adiposity and metabolic abnormalities, which mimic the clinical situation. Nevertheless, given the limitations associated with animal models, it is suggested that these results must be taken with caution. Only further behavioural studies and clinical trials will reveal the predictive validity of current preclinical model for therapeutic efficacy and metabolic side effects of OlzEt and OlzHomo.

FoR codes (2008)




Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.