Soubhye Jalal, Aldib Iyas, Prévost Martine, Elfving Betina, Gelbcke Michel, Podrecca Manuel, Conotte Raphaël, Colet Jean-Marie, Furtmüller Paul G, Delporte Cédric, Rousseau Alexandre, Vanhaeverbeek Michel, Nève Jean, Obinger Christian, Zouaoui-Boudjeltia Karim, Van Antwerpen Pierre, Dufrasne François
Laboratoire de Chimie Pharmaceutique Organique, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
J Pharm Pharmacol. 2014 Aug;66(8):1122-32. doi: 10.1111/jphp.12236. Epub 2014 Mar 27.
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.
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.
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.
Our results put forward the first hybrid molecule (compound 25) and drug (paroxetine) that can be especially used in MDD associated with inflammatory syndrome.
重度抑郁症（MDD）伴有免疫系统失衡和心血管损伤，如动脉粥样硬化。已经指出了几种机制来解释这种相当意外的关联，其中包括髓过氧化物酶（MPO）的活性。我们研究的目的是寻找同时抑制MPO和5-羟色胺转运体（SERT）的化合物，用于治疗与心血管疾病相关的MDD。
使用HEK-293 MSR细胞通过测量[³H]-5-羟色胺摄取来评估SERT抑制作用。通过对3-（氨基烷基）-5-氟吲哚衍生物和临床相关抗抑郁药进行氯胺牛磺酸试验来测定MPO抑制作用。所有动力学测量均使用温度控制的停流装置（型号SX-18 MV）进行。将有前景的先导化合物对接至使用与色氨酸复合的LeuT结构（PDB代码3F3A）建模的SERT 3D结构上。还评估了它们的毒理学概况。
侧链上有5个碳原子的3-（氨基烷基）-5-氟吲哚衍生物和帕罗西汀在纳摩尔范围内对MPO和SERT均表现出最佳活性。发现帕罗西汀是纳摩尔浓度下第一种不可逆的MPO抑制剂。
我们的结果提出了第一种可特别用于与炎症综合征相关的MDD的杂合分子（化合物25）和药物（帕罗西汀）。
