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

Xu-Feng Huang,Somayeh Jafari,Marc E Bouillon,Francesca Fernandez-Enright,Stephen G Pyne

doi:10.1186/1471-2210-12-8

Abstract

BackgroundOlanzapine 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.ResultsWe 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.ConclusionsWe 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.

Highlights

Olanzapine is an atypical antipsychotic drug with high clinical efficacy, but which can cause severe weight gain and metabolic disorders in treated patients
Changes in hormonal peptide levels correlated with food intake have been suggested to play a part in weight gain induced by atypical antipsychotic drug treatment [21]
Alteration in these distances in OlzHomo 8b and MeHomo 8a structures is involved in the lower affinity of these compounds for the dopaminergic subtype 2 (D2) and 5HT2A receptors compared to olanzapine. We suggest that both compounds 8b and 8c may present therapeutic effectiveness for treating schizophrenia. These compounds present a lower affinity for histamine 1 (H1) receptors, which may have reduced effects on weight gain and metabolic disorders than those reported with olanzapine

Summary

Introduction

Olanzapine is an atypical antipsychotic drug with high clinical efficacy, but which can cause severe weight gain and metabolic disorders in treated patients. The reduction of dopamine by typical antipsychotics is associated with an occurrence of extrapyramidal symptoms (EPS), including tardive dyskinesia (TD), dystonia, Tetracyclic compounds such as clozapine (1) and olanzapine (2) are one of the most prominent representatives for atypical antipsychotics (Figure 1). These antipsychotics showed a regional preference for the mesolimbic dopamine receptors and an optimum pKi 5HT2A/D2 binding affinity ratio [15]. A large number of studies have reported a relevant role for the affinities of atypical antipsychotics for the 5HT2A, 5HT6, 5HT7, α1A, and H1 and 5HT2C receptors in their obesogenic effects [24,25,26,27]

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Discussion

Conclusion