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Open Access Highly Accessed Research article

Novel olanzapine analogues presenting a reduced H1 receptor affinity and retained 5HT2A/D2 binding affinity ratio

Somayeh Jafari12, Marc E Bouillon2, Xu-Feng Huang13, Stephen G Pyne2 and Francesca Fernandez-Enright13*

Author affiliations

1 Center for Translational Neurosciences, Illawarra Health and Medical Research Institute, School of Health Sciences, The University of Wollongong, Wollongong, NSW, Australia

2 School of Chemistry, The University of Wollongong, Wollongong, NSW, Australia

3 Schizophrenia Research Institute, Sydney, NSW, Australia

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Citation and License

BMC Pharmacology 2012, 12:8  doi:10.1186/1471-2210-12-8

Published: 22 June 2012

Abstract

Background

Olanzapine is an atypical antipsychotic drug with high clinical efficacy, but which can cause severe weight gain and metabolic disorders in treated patients. Blockade of the histamine 1 (H1) receptors is believed to play a crucial role in olanzapine induced weight gain, whereas the therapeutic effects of this drug are mainly attributed to its favourable serotoninergic 2A and dopamine 2 (5HT2A/D2) receptor binding affinity ratios.

Results

We have synthesized novel olanzapine analogues 8a and 8b together with the already known derivative 8c and we have examined their respective in vitro affinities for the 5HT2A, D2, and H1 receptors.

Conclusions

We suggest that thienobenzodiazepines 8b and 8c with lower binding affinity for the H1 receptors, but similar 5HT2A/D2 receptor binding affinity ratios to those of olanzapine. These compounds may offer a better pharmacological profile than olanzapine for treating patients with schizophrenia.

Keywords:
Olanzapine; Novel antipsychotics; 5HT2A/D2 affinity ratio; H1 receptors