Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors

Abstract

Tetrabenazine (TBZ) ((±)-1) and dihydrotetrabenazines (DHTBZ) are potent inhibitors of VMAT2. Herein, a practical chemical resolution of (±)-1 and stereoselective synthesis of all eight DHTBZ stereoisomers are described. The result of VMAT2 binding assay revealed that (+)-1 (Ki = 4.47 nM) was 8000-fold more potent than (−)-1 (Ki = 36,400 nM). Among all eight DHTBZ stereoisomers, (2R,3R,11bR)-DHTBZ ((+)-2: Ki = 3.96 nM) showed the greatest affinity for VMAT2. The (3R,11bR)-configuration appeared to play a key role for VMAT2 binding. In summary, (+)-1, (+)-2, and their derivatives warrant further studies in order to develop more potent and safer drugs for the treatment of chorea associated with Huntington’s disease and other hyperkinetic disorders.

Valbenazine granted breakthrough drug status for treating tardive dyskinesia

“…Compounds, like tetrabenazine, dihydrotetrabenazine, amphetamine and methamphetamine, bind at distinct VMAT2 sites of this membrane protein and inhibit its activity [12][13][14]. As a result, monoamine concentrations reduce in the synaptic cleft and therefore, tardive syndromes improve.…”

“…Each enantiomer of tetrabenazine gives rise to two isomers of this dihydrotetrabenazine metabolite, so there are a total of four isomers at this stage. Of these, those derived from a-tetrabenazine are active VMAT2 inhibitors [14,[16][17][18][19]. They contribute to the therapeutic effects of the drug.…”

“…The drug itself is a one-to-one mixture of enantiomers. These are referred to as the a and b enantiomers [14,[16][17][18][19]. The carbonyl group (=O) of tetrabenazine is rapidly degraded to a hydroxyl group (-OH) of dihydrotetrabenazine via carbonyl reductase.…”

“…The a isomers can be converted to inactive O-demethylated metabolites by either of two cytochrome enzymes, CYP2D6 or CYP3A4. The b-isomers are transformed to inactive O-demethylated solely by CYP2D6 [9,14,19]. Generally, the activity of the CYP enzyme system varies between individuals and is sensitive to drug interactions, because many psychoactive compounds are degraded via this genetically determined pathway.…”

Derivatization of (±) dihydrotetrabenazine for copper-64 labeling towards long-lived radiotracers for PET imaging of the vesicular monoamine transporter 2

“…10 Resolution of (±) DTBZ was carried out based on a published procedure. 10,11 The separation was based on the existence of an interconversion between benzo[α]quinolizine and isoquinolinium upon exposure to an acid. Amino functional group was then introduced on the DTBZ molecule by following a published procedure.…”