| Abstract
| - 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 enantiomersvia 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, withalmost 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 compoundshowed 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 profilefor (S)-(+)-5. This atypical antipsychotic lead has low propensity to induce catalepsy in rat. Ithas 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 aftersubcutaneous administration. By use of 5 as the lead compound, a novel series of potentialatypical antipsychotics has been developed, some of them being characterized by a stereoselective interaction at D2 receptors. A number of structure−activity relationships trends havebeen identified, and a possible explanation is advanced in order to account for the observedstereoselectivity of the enantiomer of (±)-5 for D2 receptors. The molecular structuredetermination of the enantiomers of 5 by X-ray diffraction and molecular modeling is reported.
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