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.

A 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 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.