Design and synthesis of 2- and 3-substituted-3-phenylpropyl analogs of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine: role of amino, fluoro, hydroxyl, methoxyl, methyl, methylene, and oxo substituents on affinity for the dopamine and serotonin transporters.
J Med Chem
; 51(9): 2795-806, 2008 May 08.
Article
em En
| MEDLINE
| ID: mdl-18393401
ABSTRACT
Novel derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909, 1) and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935, 2) with various substituents in positions C2 and C3 of the phenylpropyl side chain were synthesized and evaluated for their ability to bind to the dopamine transporter (DAT) and the serotonin transporter (SERT). In the C2 series, the substituent in the S-configuration, with a lone-pair of electrons, significantly enhanced the affinity for DAT, whereas the steric effect of the substituent was detrimental to DAT binding affinity. In the C3 series, neither the lone electron pair nor the steric effect of the substituent seemed to affect DAT binding affinity, while sp (2) hybridized substituents had a detrimental effect on affinity for DAT. In the series, the 2-fluoro-substituted (S)-10 had the highest DAT binding affinity and good DAT selectivity, while the 2-amino-substituted (R)-8 showed essentially the same affinity for DAT and SERT. The oxygenated 16 and 18 possessed the best selectivity for DAT.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
/
Proteínas da Membrana Plasmática de Transporte de Dopamina
/
Proteínas da Membrana Plasmática de Transporte de Serotonina
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article