Hybrid molecules inhibiting myeloperoxidase activity and serotonin reuptake:a possible new approach of major depressive disorders with inflammatory syndrome
- Resource Type
- Authors
- Paul G. Furtmüller; Jean-Marie Colet; Christian Obinger; Jalal Soubhye; Manuel Podrecca; Raphael Conotte; Iyas Aldib; Michel Vanhaeverbeek; Pierre Van Antwerpen; Martine Prévost; Michel Gelbcke; Betina Elfving; Cédric Delporte; Karim Zouaoui-Boudjeltia; Jean Neve; Alexandre Rousseau; François Dufrasne
- Source
- Soubhye, J, Aldib, I, Prévost, M, Elfving, B, Gelbcke, M, Podrecca, M, Conotte, R, Colet, J-M, Furtmüller, P G, Delporte, C, Rousseau, A, Vanhaeverbeek, M, Nève, J, Obinger, C, Zouaoui-Boudjeltia, K, Van Antwerpen, P & Dufrasne, F 2014, ' Hybrid molecules inhibiting myeloperoxidase activity and serotonin reuptake : a possible new approach of major depressive disorders with inflammatory syndrome ', Journal of Pharmacy and Pharmacology . https://doi.org/10.1111/jphp.12236
- Subject
- Drug
medicine.medical_specialty
Serotonin
Indoles
media_common.quotation_subject
Pharmaceutical Science
Cell Line
Immune system
Internal medicine
medicine
Humans
Serotonin transporter
media_common
Peroxidase
Pharmacology
Inflammation
Serotonin Plasma Membrane Transport Proteins
Depressive Disorder, Major
biology
Chemistry
Tryptophan
medicine.disease
Paroxetine
Antidepressive Agents
Endocrinology
HEK293 Cells
Cardiovascular Diseases
Myeloperoxidase
biology.protein
Major depressive disorder
Selective Serotonin Reuptake Inhibitors
medicine.drug
- Language
- English
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 [3H]-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.