Abstract
Toludesvenlafaxine hydrochloride dihydrate is a novel chemical entity and a potential triple monoamine reuptake inhibitor. This study characterized the in vitro triple reuptake inhibition activity, antidepressant-like activity in animals, and pharmacokinetic profiles in rats of toludesvenlafaxine. Binding affinity was determined using human serotonin transporter (SERT) protein, norepinephrine transporter (NET) protein and dopamine transporter (DAT) protein, and the reuptake inhibition was determined using Chinese hamster ovary cells expressing human SERT, NET and DAT. The antidepressant-like activity was examined in rat chronic unpredictable mild stress model and olfactory bulbectomized model. In rats, the tissue distribution and pharmacokinetic parameters were determined. Toludesvenlafaxine had high binding affinity on SERT, NET and DAT, and significantly inhibited the reuptake of serotonin (IC50 = 31.4 ± 0.4 nM), norepinephrine (IC50 = 586.7 ± 83.6 nM) and dopamine (IC50 = 733.2 ± 10.3 nM) in vitro. Toludesvenlafaxine demonstrated significant antidepressant-like effects in rat models at 8–16 mg/kg. In addition, toludesvenlafaxine significantly reduced serum corticosterone and significantly increased testosterone levels in rats. Toludesvenlafaxine was quickly absorbed and converted to O-desvenlafaxine (ODV) after oral administration, both of which were selectively distributed into the hypothalamus with high concentration. Plasma ODV exposure was proportionally related to the doses after oral dosing. These results suggest that toludesvenlafaxine is a triple reuptake inhibitor with relatively fast-acting antidepressant-like activity and good therapeutic profile including improvement of anhedonia and sexual function.
Highlights
More than 350 million people across the globe suffer from major depressive disorder (MDD), which is a debilitating and refractory disease that is ranked second globally in terms of disease burden (Smith, 2014)
The primary findings of the current study were that toludesvenlafaxine demonstrated characteristic tri-reuptake inhibitor profile in vitro assays, which showed highest inhibition activity at serotonin transporter (SERT)
Toludesvenlafaxine was well-absorbed into the brain with highest drug concentration detected at hypothalamus
Summary
More than 350 million people across the globe suffer from major depressive disorder (MDD), which is a debilitating and refractory disease that is ranked second globally in terms of disease burden (Smith, 2014). Depression has become a serious global public health challenge due to its characteristics of high morbidity incidence, high suicidal rate, high recurrence rate and high disability rate (Otte et al, 2016). Pharmacological Characterization of Toludesvenlafaxine inhibitors (SSRIs), and serotonin-norepinephrine (NE) reuptake inhibitors (SNRIs). Currently available antidepressants are effective in the treatment of depression but most have various shortcomings such as delayed onset of action, limited therapeutic efficacy with modest response rate (50–70%), lack of cognitive improvement, causing sexual dysfunction and suicidal tendencies (Dupuy et al, 2011). ® monohydrate salt [DVS] is marketed as Pristiq ) which is a SNRI, was later marketed as an improved antidepressant than its parent compound, but both still have significant unwanted effects such as gastrointestinal discomfort and sexual dysfunction (Shelton, 2019). Safer and effective antidepressants are in high demand to meet the clinical needs
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