ROS-Scavenging Selenofluoxetine Derivatives Inhibit In Vivo Serotonin Reuptake

Abstract

While the neurochemistry that underpins the behavioral phenotypes of depression is the subject of many studies, oxidative stress caused by the inflammation comorbid with depression has not adequately been addressed. In this study, we described novel antidepressant−antioxidant agents consisting of selenium-modified fluoxetine derivatives to simultaneously target serotonin reuptake (antidepressant action) and oxidative stress. Excitingly, we show that one of these agents (1-F) carries the ability to inhibit serotonin reuptake in vivo in mice. We therefore present a frontier dual strategy that paves the way for the future of antidepressant therapies.

SSRI antidepressants differentially modulate serotonin reuptake and release in Drosophila

“…Our data for escitalopram in Drosophila does not show a hybrid uptake mechanism and relies more on the slow, Uptake 1 mechanism. Interestingly, in several previous studies in Hashemi lab, they looked at serotonin reuptake dynamics for citalopram (Hashemi et al, 2012), escitalopram (Wood & Hashemi, 2013), and fluoxetine (Ribaudo et al, 2021), and our t 50 values in Drosophila are very similar to their in vivo data in mice, which is shown in Table 2. They also saw similar trends where fluoxetine requires higher doses to elicit concentration changes compared with citalopram and escitalopram (Hashemi et al, 2012; Ribaudo et al, 2021; Wood & Hashemi, 2013).…”

“…Interestingly, in several previous studies in Hashemi lab, they looked at serotonin reuptake dynamics for citalopram (Hashemi et al, 2012), escitalopram (Wood & Hashemi, 2013), and fluoxetine (Ribaudo et al, 2021), and our t 50 values in Drosophila are very similar to their in vivo data in mice, which is shown in Table 2. They also saw similar trends where fluoxetine requires higher doses to elicit concentration changes compared with citalopram and escitalopram (Hashemi et al, 2012; Ribaudo et al, 2021; Wood & Hashemi, 2013). Thus, reuptake and turnover kinetics are equivalent and concentration changes are similar, which indicates that Drosophila can be used in pharmacological assays to understand reuptake and concentration changes with genetic mutants that are easier to create with this model.…”

Current Trends in Computational Quantum Chemistry Studies on Antioxidant Radical Scavenging Activity

“… 118 It has been recently evidenced that Gibbs free energy is actually proportional to the activation energy of hydrogen atom transfer, and hence reaction rate of this mechanism. 90 , 268 , 269 …”

“…On the other hand, ignoring a reaction path due to difficulties in locating a transition state may result in a more significant error than accepting the given rule wihout its confirmation, especially if it was discovered to hold true for a structurally similar compounds . It has been recently evidenced that Gibbs free energy is actually proportional to the activation energy of hydrogen atom transfer, and hence reaction rate of this mechanism. ,, …”

From a Molecule to a Drug: Chemical Features Enhancing Pharmacological Potential

“…Combining our complementary expertise, we recently developed a project repurposing or better redesigning a popular antidepressant drug molecule, i.e., fluoxetine, which is better known by its commercial name, Prozac. We designed in silico a series of selenoderivatives of fluoxetine and assessed their enhanced antioxidant capacity through chemical and computational protocols [1,2], and, finally, we demonstrated in vivo that selenofluoxetine maintains its SSRI antidepressant action [3]. These outcomes paved the route to our contribution on this Special Issue, in which we report on a new ability of these selenofluoxetine derivatives, i.e., a novel strategy to selectively release bioactive molecules within a selenoxide elimination-triggered enamine hydrolysis [4].…”