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

Abstract

Aim: To separate and evaluate 9-cyclopropylmethoxy-dihydrotetrabenazine (13a) and its stereoisomers for their high affinity for vesicular monoamine transporter-2 (VMAT2). Method: Stereoisomers of 13a were separated and configurations were ascertained by chiral chromatography and crystal diffraction combined with 1H-1H NOESY assay. Possible binding modes of eight stereoisomers and VMAT2 were explored by molecular docking assays. TheVMAT2 affinity of thestereoisomers, inhibition in vivoand pharmacokinetics in rats were evaluated. Results: Three stereoisomers were obtained: P1, P2and P3, and all had similar VMAT2 binding modes. P2 [(2R, 3R, 11bR)-13a] showed the highest potential VMAT2 binding activity (Ki=0.75 nM), decreased locomotor activity in ratsand had anoral absolute bioavailability of 92.0%. Conclusion: P2 has good efficacy and pharmacokinetic properties and warrants further development to treat tardive dyskinesia.