Absolute configuration of (+)-α-dihydrotetrabenazine, an active metabolite of tetrabenazine

Abstract

Chiral column liquid chromatography and enantiospecific enzymatic hydrolysis were utilized to separate the enantiomers of α- and Β-dihydrotetrabenazine and α-9-O-desmethyldihydrotetrabenazine, three benzo[a]quinolizines derived from the amine-depleting drug tetrabenazine. An X-ray crystal structure analysis of (−)-α-9-O-desmethyldihydrotetrabenazine gave an absolute structure of that compound as the 2 S , 3 S , 11b S isomer. Therefore, (−)-α-dihydrotetrabenazine also has the 2 S , 3 S , 11b S absolute configuration. (+)-α-Dihydrotetrabenazine, the single biologically active isomer from the metabolic reduction of tetrabenazine, thus has the absolute configuration of 2 R , 3 R , 11b R . For further in vitro and in vivo studies of the vesicular monoamine transporter, it is now possible to use the single enantiomer of radiolabeled α-dihydrotetrabenazine. Chirality 9:59–62, 1997. © 1997 Wiley-Liss, Inc.