New antipsychotic agents with serotonin and dopamine antagonist properties based on a pyrrolo[2,1-b][1,3]benzothiazepine structure

Giuseppe Campiani, Vito Nacci, Susanna Bechelli, Silvia M. Ciani, Antonio Garofalo, Isabella Fiorini, Håkan Wikström, Peter De Boer, Yi Liao, Pieter G. Tepper, Alfredo Cagnotto, Tiziana Mennini

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)3763-3772
Number of pages10
JournalJournal of Medicinal Chemistry
Volume41
Issue number20
DOIs
Publication statusPublished - Sep 24 1998

ASJC Scopus subject areas

  • Organic Chemistry

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