| Autor: |
Campiani, G., Butini, S., Gemma, S., Nacci, V., Fattorusso, C., Catalanotti, B., Giorgi, G., Cagnotto, A., Goegan, M., Mennini, T., Minetti, P., Cesare, M. A. Di, Mastroianni, D., Scafetta, N., Galletti, B., Stasi, M. A., Castorina, M., Pacifici, L., Ghirardi, O., Tinti, O., Carminati, P. |
| Zdroj: |
Journal of Medicinal Chemistry; January 2002, Vol. 45 Issue: 2 p344-359, 16p |
| Abstrakt: |
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. |
| Databáze: |
Supplemental Index |
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