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

  • Eur J Med Chem. 2011 May;46(5):1841-8. doi: 10.1016/j.ejmech.2011.02.046.
Zhangyu Yao  1 ,  Xueying Wei ,  Xiaoming Wu ,  Jonathan L Katz ,  Theresa Kopajtic ,  Nigel H Greig ,  Hongbin Sun
Affiliations
  • 1. Center for Drug Discovery, College of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
PMID: 21396745 DOI: 10.1016/j.ejmech.2011.02.046
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.

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