New Antipsychotic Agents with Serotonin and Dopamine Antagonist Properties Based on a Pyrrolo[2,1-b][1,3]benzothiazepine Structure

The development of a synthetic approach to the novel pyrrolo[2,1- b][1,3]benzothiazepine and its derivatives and their biological evaluation as potential antipsychotic drugs are described. In binding studies these compounds proved to be potent 5-HT2, D2, and D3 receptor ligands. The more potent benzothiazepine (±)-3b was resolved into its enantiomers by using HPLC techniques. In vitro testing confirmed that (-)-3b is a more potent D2 receptor ligand, maintaining high affinity for 5-HT2 receptors. In contrast, the (+)-3b enantiomer presents a 35 times higher affinity for 5-HT2 than for dopamine D2 receptors with a similar dopamine D1 receptor affinity to that of (-)-3b. Overall, (+)-3b shows an 'atypical' neuroleptic binding profile, while (-)-3b has a more 'classical' profile. Furthermore pharmacological and biochemical testing displayed that the novel benzothiazepine (±)-3b is able to increase the extracellular levels of dopamine in the rat striatum and causes a dose-related suppression of apomorphine-induced locomotor activity. At low doses (±)-3b does not induce catalepsy, showing atypical antipsychotic properties similar to those of olanzapine. These heterocyclic compounds represent new leads for the development of novel antipsychotic drugs with atypical properties.