Pharmacological Characterization of Toludesvenlafaxine as a Triple Reuptake Inhibitor

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.

Epigenetic Mechanism of 5-HT/NE/DA Triple Reuptake Inhibitor on Adult Depression Susceptibility in Early Stress Mice

“…LPM570065 (also known as LY03005, ansofaxine, and toludesvenlafaxine) ( Figure 1 ) is a new chemical entity and a 5-HT/NE/DA triple reuptake inhibitor. LPM570065 exhibits high binding affinity to serotonin transporter (SERT), norepinephrine transporter (NET) and dopamine transporter (DAT), and increases the release of 5-HT, NE and DA in the striatum after oral administration ( Zhu et al, 2021 ). In several preclinical models including the forced swimming test, the chronic unpredictable mild stress model and the olfactory bulbectomized model, LPM570065 demonstrated significant antidepressant-like effects ( Zhang et al, 2014 ; Zhu et al, 2021 ).…”

“…LPM570065 exhibits high binding affinity to serotonin transporter (SERT), norepinephrine transporter (NET) and dopamine transporter (DAT), and increases the release of 5-HT, NE and DA in the striatum after oral administration ( Zhu et al, 2021 ). In several preclinical models including the forced swimming test, the chronic unpredictable mild stress model and the olfactory bulbectomized model, LPM570065 demonstrated significant antidepressant-like effects ( Zhang et al, 2014 ; Zhu et al, 2021 ). In a phase II clinical study, LPM570065 extended-release tablet was safe, well-tolerated, and effective in improving depression symptoms in MDD patients ( Mi et al, 2021 ), suggesting that LPM570065 could be a useful treatment option for MDD patients.…”

A Phase 3, Multicenter, Double-blind, Randomized, Placebo-controlled Clinical Trial to Verify the Efficacy and Safety of Ansofaxine (LY03005) for Major Depressive Disorder

“…The active ingredient of ansofaxine (ansofaxine hydrochlorideis) is phydroxybenzoic acid (PHBA) of an O-desmethylvenlafaxine (ODV). Both ansofaxine and ODV could enter the central nervous system and selectively distribute into the hypothalamus with a certain concentration to implement therapeutic effect [23]. ODV is also the metabolism of venlafaxine, a double reuptake inhibitor of 5-HT and NE, with a stronger inhibition on 5-HT reuptake and a weak affinity for α receptor, D2 receptor, 5-HT1A and 5-HT2 receptor, opioid receptor and benzodiazepine binding sites.…”

“…Ansofaxine, with high affinities to the dopamine transporter (DAT), the norepinephrine transporter (NET) and the serotonin transporter (SERT), and significant inhibition of the reuptake of DA, NE and 5-HT, is a potential TRIs for MDD treatment [22,23]. For preclinical studies, ansofaxine was negative in the genotoxicity combination studies and had an acceptable toxicity profiles in the general toxicity studies, fertility and early embryonic development studies and good safety and tolerability properties in safety studies [23.24.25].For clinical trials, ansofaxine displayed a dose-proportional pharmacokinetic characteristics in Phase 1 studies in healthy adult with the dose range of 20-200 mg. After 3 sequent dose of 40-160 mg per day, plasma concentration of ansofaxine could reach steady state with an average half-life of 9-10 h and diet did not show a significant effect on the pharmacokinetics.…”

Efficacy, Tolerability, and Safety of Toludesvenlafaxine for the Treatment of Major Depressive Disorder—A Narrative Review

“…The antidepressant effects were observed in rodent models at 8–16 mg/kg [ 46 ]. The absorption was good after oral administration, and it was converted to O-desvenlafaxine due to the action of esterases in vivo, both reaching the hypothalamus in high concentration [ 81 ]. The plasma exposure was proportional to the dose after oral administration [ 81 ].…”