Department of Organic Chemistry, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 2 dr. A. Jurasza St., 85-094 Bydgoszcz, Poland.
Int J Mol Sci. 2021 Jun 11;22(12):6293. doi: 10.3390/ijms22126293.
Thus far, many hypotheses have been proposed explaining the cause of depression. Among the most popular of these are: monoamine, neurogenesis, neurobiology, inflammation and stress hypotheses. Many studies have proven that neurogenesis in the brains of adult mammals occurs throughout life. The generation of new neurons persists throughout adulthood in the mammalian brain due to the proliferation and differentiation of adult neural stem cells. For this reason, the search for drugs acting in this mechanism seems to be a priority for modern pharmacotherapy. Paroxetine is one of the most commonly used antidepressants. However, the exact mechanism of its action is not fully understood. The fact that the therapeutic effect after the administration of paroxetine occurs after a few weeks, even if the levels of monoamine are rapidly increased (within a few minutes), allows us to assume a neurogenic mechanism of action. Due to the confirmed dependence of depression on serotonin, norepinephrine, dopamine and γ-aminobutyric acid levels, studies have been undertaken into paroxetine interactions with these primary neurotransmitters using in silico and in vitro methods. We confirmed that paroxetine interacts most strongly with monoamine transporters and shows some interaction with γ-aminobutyric acid transporters. However, studies of the potency inhibitors and binding affinity values indicate that the neurogenic mechanism of paroxetine's action may be determined mainly by its interactions with serotonin transporters.
到目前为止，已经提出了许多解释抑郁症病因的假说。其中最受欢迎的有：单胺假说、神经发生假说、神经生物学假说、炎症假说和应激假说。许多研究已经证明，成年哺乳动物大脑中的神经发生贯穿一生都在发生。由于成年神经干细胞的增殖和分化，哺乳动物大脑中的新神经元的产生在整个成年期都持续存在。因此，寻找作用于该机制的药物似乎是现代药物治疗的优先事项。帕罗西汀是最常用的抗抑郁药之一。然而，其作用的确切机制尚未完全阐明。帕罗西汀给药后治疗效果在几周后才出现的事实，即使单胺水平迅速升高（在几分钟内），这让我们假设其作用机制具有神经发生作用。由于已经证实抑郁症与 5-羟色胺、去甲肾上腺素、多巴胺和γ-氨基丁酸的水平有关，因此已经使用计算机模拟和体外方法研究了帕罗西汀与这些主要神经递质的相互作用。我们证实，帕罗西汀与单胺转运体的相互作用最强，并显示出与γ-氨基丁酸转运体的一些相互作用。然而，对效力抑制剂和结合亲和力值的研究表明，帕罗西汀作用的神经发生机制可能主要取决于其与 5-羟色胺转运体的相互作用。
