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

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.

Figure 1

Structures of tetracyclic atypical antipsychotics.

Scheme 1

Synthesis of compounds 8a, 8b, and 8c. Reagents and conditions: (i) 1-fluoro-2-nitrobenzene, NaH, THF, rt, 20 h, 60%; (ii) SnCl₂, EtOH, 80°C, 1 h, 80%; (iiia) N-methylhomopiperazine (5 equiv), no solvent, microwave heating, 80°C, 4 h,65%; (iiib) N-methylhomopiperazine (5 equiv), no solvent, microwave heating, 120°C, 3 h, 55%; (iiic) N-methylpiperazine (10 equiv), N-methylpiperazine hydrochloride (10 equiv), DMSO, 110–120°C, 20 h, 56%.

Figure 2

Procedure for the synthesis of compound (2-ethyl-4-(4′-methylpiperazin-1′-yl)-10Hbenzo[b]thieno[2,3-e][1,4]diazepine (8c).

Figure 3

Procedure for the synthesis of compound (2-ethyl-4-(4′-methyl-1′,4′-diazepan-1′-yl)-10H-benzo[b]thieno[2,3-e] [1,4]diazepine (8b).

Figure 4

Procedure for the synthesis of compound (2-methyl-4-(4′-methyl-1′,4′-diazepan-1′-yl)-10H-benzo[b]thieno[2,3-e] [1,4]diazepine (8a).