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.
Campiani, G., Butini, S., Gemma, S., Nacci, V., Fattorusso, C., Catalanotti, B., et al. (2002). Pyrrolo 1,3 benzothiazepine-based Atypical Antipsychotic Agents. Synthesis, Structure-Activity Relationship, Molecular Modeling, and Biological Studies. JOURNAL OF MEDICINAL CHEMISTRY, 45(2), 344-359 [10.1021/jm010982y].
Pyrrolo 1,3 benzothiazepine-based Atypical Antipsychotic Agents. Synthesis, Structure-Activity Relationship, Molecular Modeling, and Biological Studies
Campiani, Giuseppe;Butini, Stefania;Gemma, Sandra;Nacci, Vito;Giorgi, Gianluca;
2002-01-01
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 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.File | Dimensione | Formato | |
---|---|---|---|
2002_jmc_antips.pdf
non disponibili
Tipologia:
Abstract
Licenza:
NON PUBBLICO - Accesso privato/ristretto
Dimensione
292.46 kB
Formato
Adobe PDF
|
292.46 kB | Adobe PDF | Visualizza/Apri Richiedi una copia |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
https://hdl.handle.net/11365/19281
Attenzione
Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo