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

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.

Graphical abstractA practical chemical resolution of tetrabenazine ((±)-1) and stereoselective synthesis of all eight dihydrotetrabenazine stereoisomers are described. The result of VMAT2 binding assay revealed that (+)-1 was 8000-fold more potent than (−)-1.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► We carry out a practical chemical resolution of tetrabenazine (TBZ). ► All eight stereoisomers of dihydrotetrabenazines (DHTBZ) have been synthesized. ► (+)-TBZ is 8000-fold more potent than (—)-TBZ. ► The (3R,11bR)-configuration plays a key role for TBZ and DHTBZ binding to VMAT2. ► (2R,3R,11bR)-DHTBZ warrants further study as a potential drug for treating Huntington's disease.