title: Hybrid molecules inhibiting myeloperoxidase activity and serotonin reuptake: a possible new approach of major depressive disorders with inflammatory syndrome.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
authors.affiliation: Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Jalal
authors.initials: J
authors.lastname: Soubhye
authors.forename: Iyas
authors.initials: I
authors.lastname: Aldib
authors.forename: Martine
authors.initials: M
authors.lastname: Prévost
authors.forename: Betina
authors.initials: B
authors.lastname: Elfving
authors.forename: Michel
authors.initials: M
authors.lastname: Gelbcke
authors.forename: Manuel
authors.initials: M
authors.lastname: Podrecca
authors.forename: Raphaël
authors.initials: R
authors.lastname: Conotte
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Colet
authors.forename: Paul G
authors.initials: PG
authors.lastname: Furtmüller
authors.forename: Cédric
authors.initials: C
authors.lastname: Delporte
authors.forename: Alexandre
authors.initials: A
authors.lastname: Rousseau
authors.forename: Michel
authors.initials: M
authors.lastname: Vanhaeverbeek
authors.forename: Jean
authors.initials: J
authors.lastname: Nève
authors.forename: Christian
authors.initials: C
authors.lastname: Obinger
authors.forename: Karim
authors.initials: K
authors.lastname: Zouaoui-Boudjeltia
authors.forename: Pierre
authors.initials: P
authors.lastname: Van Antwerpen
authors.forename: François
authors.initials: F
authors.lastname: Dufrasne
mesh_terms: D000928:Antidepressive Agents / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000378:metabolism; D002460:Cell Line; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D009195:Peroxidase / Q000037:antagonists & inhibitors*; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D007211:Indoles; D009195:Peroxidase; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C095066:5-fluoroindole
keywords: atherosclerosis; depression; irreversible inhibitor; myeloperoxidase; serotonin