Abstract
Valbenazine and deutetrabenazine are the only two therapeutic drugs approved for tardive dyskinesia based on blocking the action of vesicular monoamine transporter 2 (VMAT2). But there exist demethylated inactive metabolism at the nine position for both them resulting in low availability, and CYP2D6 plays a major role in this metabolism resulting in the genetic polymorphism issue. 9-trifluoroethoxy-dihydrotetrabenazine (13e) was identified as a promising lead compound for treating tardive dyskinesia. In this study, we separated 13e via chiral chromatography and acquired R,R,R-13e [(+)-13e] and S,S,S-13e [(−)-13e], and we investigated their VMAT2-inhibitory activity and examined the related pharmacodynamics and pharmacokinetics properties using in vitro and in vivo models (+)-13e displayed high affinity for VMAT2 (Ki = 1.48 nM) and strongly inhibited [3H]DA uptake (IC50 = 6.11 nM) in striatal synaptosomes. Conversely, its enantiomer was inactive. In vivo, (+)-13e decreased locomotion in rats in a dose-dependent manner. The treatment had faster, stronger, and longer-lasting effects than valbenazine at an equivalent dose. Mono-oxidation was the main metabolic pathway in the liver microsomes and in dog plasma after oral administration, and glucuronide conjugation of mono-oxidized and/or demethylated products and direct glucuronide conjugation were also major metabolic pathways in dog plasma. O-detrifluoroethylation of (+)-13e did not occur. Furthermore, CYP3A4 was identified as the primary isoenzyme responsible for mono-oxidation and demethylation metabolism, and CYP2C8 was a secondary isoenzyme (+)-13e displayed high permeability across the Caco-2 cell monolayer, and it was not a P-glycoprotein substrate as demonstrated by its high oral absolute bioavailability (75.9%) in dogs. Thus, our study findings highlighted the potential efficacy and safety of (+)-13e in the treatment of tardive dyskinesia. These results should promote its clinical development.
Highlights
Tardive dyskinesia (TD) is a movement disorder occurring after long-term treatment with dopamine antagonists such as typical or atypical antipsychotics and certain antidepressants (Albayrak and Ekinci, 2012; Waln and Jankovic, 2013)
The single crystals of these two main isomers’ p-toluenesulfonate were respectively grown from methanol solution via slow evaporation at room temperature
Both crystals formed colorless blocks, and the crystallographic data and refinement details are listed in Table 1, and their molecular ellipsoid diagrams are presented in Figure 2, which illustrated that one is the p-toluenesulfonate of (2R,3R,11bR) isomer, with the free base of (+)-9-(2,2,2trifluoroethoxy)-α-dihydrotetrabenazine [(+)-13e] (DOI: 10. 5517/ccdc.csd.cc28v81g, CSD Communication (CCDC deposition number 2110605)
Summary
Tardive dyskinesia (TD) is a movement disorder occurring after long-term treatment with dopamine antagonists such as typical or atypical antipsychotics and certain antidepressants (Albayrak and Ekinci, 2012; Waln and Jankovic, 2013). The prevalence of TD remains substantial in patients treated with atypical (20%). Vesicular monoamine transporter 2 (VMAT2), expressed in the neuronal cells of the central nervous system and sympathetic adrenal chromaffin cells, is responsible for the uptake of cytosolic monoamines, including serotonin, norepinephrine, histamine, and dopamine, into synaptic vesicles in monoaminergic neurons (Liu and Edwards, 1997; Wimalasena, 2011; Lohr et al, 2017). VMAT2 inhibitors block the action of VMAT2 and inhibit its activity, thereby reducing the uptake and storage of monoamines from the cytoplasm to presynaptic vesicles and resulting in reduced concentrations of monoamines, which counteracts the increased activity of the dopamine system (Mulvihill, 2019)
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