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

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 (5HT_2A/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 5HT_2A, D₂, and H₁ receptors. Conclusions: We suggest that thienobenzodiazepines 8b and 8c with lower binding affinity for the H₁ receptors, but similar 5HT_2A/D₂ receptor binding affinity ratios to those of olanzapine. These compounds may offer a better pharmacological profile than olanzapine for treating patients with schizophrenia. [ABSTRACT FROM AUTHOR]