Hybrid molecules inhibiting myeloperoxidase activity and serotonin reuptake: a possible new approach of major depressive disorders with inflammatory syndrome.
J Pharm Pharmacol
; 66(8): 1122-32, 2014 Aug.
Article
en En
| MEDLINE
| ID: mdl-24673477
OBJECTIVES: Major depressive disorder (MDD) is accompanied with an imbalance in the immune system and cardiovascular impairments, such as atherosclerosis. Several mechanisms have been pointed out to underlie this rather unexpected association, and among them the activity of myeloperoxidase (MPO). The aim of our study was to find compounds that inhibit both MPO and serotonin transporter (SERT) for treating MDD associated with cardiovascular diseases. METHODS: SERT inhibition was assessed with measuring of [(3) H]-serotonin uptake using HEK-293 MSR cells. MPO inhibition was determined by taurine chloramine test on 3-(aminoalkyl)-5-fluoroindole derivatives and on clinically relevant antidepressants. All kinetic measurements were performed using a temperature-controlled stopped-flow apparatus (model SX-18 MV). Promising lead compounds were docked onto SERT 3D structure modelled using the LeuT structure complexed to tryptophan (PDB code 3F3A). Their toxicological profile was also assessed. KEY FINDINGS: 3-(aminoalkyl)-5-fluoroindole derivative with 5 carbons on the side chain and paroxetine showed the best activity on both MPO and SERT at the nanomolar range. Paroxetine was found to be the first irreversible MPO inhibitor at nanomolar concentrations. CONCLUSIONS: Our results put forward the first hybrid molecule (compound 25) and drug (paroxetine) that can be especially used in MDD associated with inflammatory syndrome.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Serotonina
/
Inhibidores Selectivos de la Recaptación de Serotonina
/
Peroxidasa
/
Trastorno Depresivo Mayor
/
Proteínas de Transporte de Serotonina en la Membrana Plasmática
/
Inflamación
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Pharm Pharmacol
Año:
2014
Tipo del documento:
Article
País de afiliación:
Bélgica
Pais de publicación:
Reino Unido