Deutetrabenazine Targets VMAT2 With Precision, Analysis Finds
Deutetrabenazine showed significant efficacy and high specificity in inhibiting its primary target, vesicular monoamine transporter type 2 (VMAT2), in functional assessments of the drug’s deuterated metabolites. A Teva research team reported the findings at the inaugural poster session at the NEI Spring Congress in Philadelphia, Pennsylvania.
Deutetrabenazine is approved for the treatment of tardive dyskinesia and chorea associated with Huntington disease in adults.
“After oral administration, deutetrabenazine is extensively metabolized by carbonyl reductase into 4 deuterated metabolites: (+/-) α-dihydrotetrabenazine (+/- α-HTBZ) and (+/-) β-dihydrotetrabenazine (+/- β-HTBZ),” wrote Noa Barak Broner, PhD, of Teva Pharmaceutical Industries Limited, Netanya, Isreal, and coauthors in the poster abstract. “In this study, we conducted a comprehensive pharmacological evaluation of the 4 metabolites, with a particular emphasis on their functional activity against the primary pharmacological target, VMAT2, and potential secondary targets.”
Functional assays confirmed [+] metabolites were the active moieties that inhibited VMAT2, according to the abstract. Half-maximal inhibitory concentrations of [+] metabolites were around 10 nM compared with more than 1000 nM for [–] metabolites.
Functional assessments also confirmed the absence of secondary targets, with a single exception: the serotonin 5HT7 receptor. Researchers reported an antagonistic effect to the receptor, with half-maximal inhibitory concentrations of both [–]-α-HTBZ and [–]-β-HTBZ less than 280 nM in functional assays.
“Current literature provides no evidence for adverse events related to 5HT7 antagonism and suggests that there could even be potential positive effects of this binding,” the authors wrote. “These results highlight the precision of deutetrabenazine’s active deuterated metabolites in targeting VMAT2 and reinforce the clinically established favorable safety profile of deutetrabenazine.”
The study was funded by Teva Pharmaceutical Industries Ltd.
Reference
Broner NB, Magid L, Griffin T, Schmukler E, Fishbein I. Potency and specificity of deutetrabenazine deuterated metabolites for VMAT2 as confirmed by binding affinity and functional activity studies. Poster presented at the NEI Spring Congress; May 8-10, 2025; Philadelphia, Pennsylvania.
