Synthesis and analysis of dihydrotetrabenazine derivatives as novel vesicular monoamine transporter 2 inhibitors

Vesicular monoamine transporter 2 (VMAT2) is essential for synaptic transmission of all biogenic amines in the brain including serotonin, norepinephrine, histamine, and dopamine (DA). Given its crucial role in the neurophysiology and pharmacology of the central nervous system, VMAT2 is recognized as an important therapeutic target for various neurological disorders such as tardive dyskinesia (TD). Here, a novel series of dihydrotetrabenazine derivative analogs were designed and synthesized to evaluate their effects on [H-3]dihydrotetrabenazine (DTBZ) binding and [H-3]DA uptake at VMAT2. Of these analogs, compound 13e showed a high binding affinity for VMAT2 (IC50 = 5.13 +/- 0.16 nM) with excellent inhibition of [H-3]DA uptake (IC50 = 6.04 +/- 0.03 nM) in striatal synaptosomes. In human liver microsomes, 13e was more stable (T-1/2 = 161.2 min) than other reported VMAT2 inhibitors such as DTBZ (T-1/2 = 119.5 min). In addition, 13e effectively inhibited the spontaneous locomotor activity (percent inhibition at 3 mu mol/kg = 64.7%) in Sprague-Dawley rats. Taken together, our results indicate that 13e might be a promising lead compound for the development of novel treatments of TD. (C) 2021 Published by Elsevier Masson SAS.

Automated summary

A novel series of dihydrotetrabenazine derivative analogs were synthesized and evaluated for their effects on VMAT2, with compound 13e showing promising affinity and inhibition. This compound also exhibited increased stability compared to other VMAT2 inhibitors and effectively suppressed locomotor activity in rats, suggesting its potential as a lead compound for TD treatment development.