Pyrrolo[1,3]benzothiazepine-based atypical antipsychotic agents. Synthesis, structure - Activity relationship, molecular modeling, and biological studies

Giuseppe Campiani, Stefania Butini, Sandra Gemma, Vito Nacci, Caterina Fattorusso, Bruno Catalanotti, Gianluca Giorgi, Alfredo Cagnotto, Mara Goegan, Tiziana Mennini, Patrizia Minetti, M. Assunta Di Cesare, Domenico Mastroianni, Nazzareno Scafetta, Bruno Galletti, M. Antonietta Stasi, Massimo Castorina, Licia Pacifici, Orlando Ghirardi, Ornella TintiPaolo Carminati

Research output: Contribution to journalArticlepeer-review


The prototypical dopamine and serotonin antagonist (±)-7-chloro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b] [1,3]benzothiazepine (5) was resolved into its R and S enantiomers via crystallization of the diastereomeric tartaric acid salts. Binding studies confirmed that the (R)-(-)-enantiomer is a more potent D2 receptor antagonist than the (S)-(+)-enantiomer, with almost identical affinity at the 5-HT2 receptor ((S)-(+)-5, log Y = 4.7; (R)-(-)-5, log Y = 7.4). These data demonstrated a significant stereoselective interaction of 5 at D2 receptors. Furthermore, enantiomer (S)-(+)-5 (ST1460) was tested on a panel of receptors; this compound showed an intriguing binding profile characterized by high affinity for H1 and the α1 receptor, a moderate affinity for α2 and D3 receptors, and low affinity for muscarinic receptors. Pharmacological and biochemical investigation confirmed an atypical pharmacological profile for (S)-(+)-5. This atypical antipsychotic lead has low propensity to induce catalepsy in rat. It has minimal effect on serum prolactin levels, and it has been selected for further pharmacological studies. (S)-(+)-5 increases the extracellular levels of dopamine in the rat striatum after subcutaneous administration. By use of 5 as the lead compound, a novel series of potential atypical antipsychotics has been developed, some of them being characterized by a stereoselective interaction at D2 receptors. A number of structure - activity relationships trends have been identified, and a possible explanation is advanced in order to account for the observed stereoselectivity of the enantiomer of (±)-5 for D2 receptors. The molecular structure determination of the enantiomers of 5 by X-ray diffraction and molecular modeling is reported.

Original languageEnglish
Pages (from-to)344-359
Number of pages16
JournalJournal of Medicinal Chemistry
Issue number2
Publication statusPublished - Jan 17 2002

ASJC Scopus subject areas

  • Organic Chemistry


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