Synthesis and biological evaluation of meperidine analogues at monoamine transporters.
J Med Chem
; 48(5): 1336-43, 2005 Mar 10.
Article
en En
| MEDLINE
| ID: mdl-15743177
ABSTRACT
A series of aryl-substituted meperidine analogues was synthesized, and the binding affinities were determined at the DAT, SERT, and NET as well as at mu-opioid receptors. Generally the analogues exhibited increased affinity for the DAT and SERT relative to meperidine but exhibited low binding affinity for the NET. The 2-naphthyl derivative 7f was the most potent ligand at the SERT (K(i) = 0.0072 muM) and was the most selective ligand for the SERT over the DAT (DAT/SERT = 158) and mu-opioid receptors (mu/SERT = 281). The 3,4-dichlorophenyl derivative 7e was the most potent ligand at the DAT (K(i) = 0.125 muM) and was the most selective ligand for the DAT over mu-opioid receptors (mu/DAT = 16.3) but remained slightly more selective for the SERT over the DAT(DAT/SERT = 6.68). Three compounds, the 3,4-dichlorophenyl derivative 7e and the 2-naphthyl analogues 6f and 7f, were identified that were more potent at the DAT than meperidine and that exhibited well-defined biphasic dopamine uptake inhibition similar to meperidine. However, none of the analogues tested produced locomotor effects or substituted for cocaine in drug discrimination studies, suggesting that the mu-opioid effects of these analogues may contribute to the poor efficacy observed in vivo.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Proteínas de Transporte de Membrana
/
Glicoproteínas de Membrana
/
Simportadores
/
Meperidina
/
Proteínas del Tejido Nervioso
Límite:
Animals
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2005
Tipo del documento:
Article
País de afiliación:
Estados Unidos