9-Cyclopropylmethoxy-dihydrotetrabenazine and its stereoisomers as vesicular monoamine transporter-2 inhibitors.

To separate and evaluate 9-cyclopropylmethoxy-dihydrotetrabenazine (13a) and its stereoisomers for their high affinity for vesicular monoamine transporter-2 (VMAT2). Stereoisomers of 13a were separated and configurations were ascertained by chiral chromatography and crystal diffraction combined with H-H NOESY assay. Possible binding modes of eight stereoisomers and VMAT2 were explored by molecular docking assays. The VMAT2 affinity of the stereoisomers, inhibition  and pharmacokinetics in rats were evaluated. Three stereoisomers were obtained: P1, P2 and P3, and all had similar VMAT2 binding modes. P2 [(2, 3, 11b)-13a] showed the highest potential VMAT2 binding activity ( = 0.75 nM), decreased locomotor activity in rats and had an oral absolute bioavailability of 92.0%. P2 has good efficacy and pharmacokinetic properties and warrants further development to treat tardive dyskinesia.