Haloperidol‐Induced Preclinical Tardive Dyskinesia Model in Rats

Gúzen, Fausto Pierdoná; Cavalcanti, José Rodolfo Lopes de Paiva; Cavalcanti, Diogo Manuel Lopes de Paiva; Sales, Luma Gabrielle Praxedes de; Silva, Monalisa Stefany Martins da; Silva, Aline Naiara Azevedo da; Pinheiro, Francisco Irochima; Araújo, Dayane Pessoa de

doi:10.1002/cpns.68

Cited by 8 publications

(1 citation statement)

References 17 publications

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“…The aforementioned PK characteristics are undoubtedly helpful for obtaining good PD results in vivo . VMAT2 inhibitors can inhibit the release of dopamine and reduce rat locomotor activity, which is used as a substitute index to evaluate the efficacy of VMAT2 inhibitors ( Grigoriadis et al, 2017 ; Guzen et al, 2019 ; Li et al, 2019 ). The multi-target activity screen of SpectrumScreen ® Panel (Eurofins screen) demonstrated that (+)-13e had no effects on dopamine receptors, serotonin receptors, adrenergic receptors, dopamine transporter, norepinephrine transporter, five serotonin transporter, and so on.…”

Section: Discussionmentioning

confidence: 99%

(+)-9-Trifluoroethoxy-α-Dihydrotetrabenazine as a Highly Potent Vesicular Monoamine Transporter 2 Inhibitor for Tardive Dyskinesia

Wang

Lin

et al. 2021

Front. Pharmacol.

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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.

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Section: Discussionmentioning

confidence: 99%