Pyrrolo[1,3]benzothiazepine-Based Atypical Antipsychotic Agents. Synthesis, Structure-Activity Relationship, Molecular Modeling, and Biological Studies

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.