Development of Thiazolidinedione-Based HDAC6 Inhibitors to Overcome Methamphetamine Addiction

Int J Mol Sci. 2019 Dec 9;20(24):6213. doi: 10.3390/ijms20246213.

Abstract

Thiazolidinedione is a five-membered heterocycle that is widely used in drug discovery endeavors. In this study, we report the design, synthesis, and biological evaluation of a series of thiazolidinedione-based HDAC6 inhibitors. In particular, compound 6b exerts an excellent inhibitory activity against HDAC6 with an IC50 value of 21 nM, displaying a good HDAC6 selectivity over HDAC1. Compound 6b dose-dependently induces the acetylation level of α-tubulin via inhibition of HDAC6 in human neuroblastoma SH-SY5Y cell line. Moreover, compound 6b efficiently reverses methamphetamine-induced morphology changes of SH-SY5Y cells via regulating acetylation landscape of α-tubulin. Collectively, compound 6b represents a novel HDAC6-isoform selective inhibitor and demonstrates promising therapeutic potential for the treatment of methamphetamine addiction.

Keywords: HDAC6 inhibitors; drug addiction; methamphetamine; thiazolidinedione.

MeSH terms

  • Amphetamine-Related Disorders / drug therapy
  • Amphetamine-Related Disorders / enzymology
  • Cell Line, Tumor
  • Drug Discovery*
  • Histone Deacetylase 6 / antagonists & inhibitors*
  • Histone Deacetylase 6 / chemistry
  • Histone Deacetylase 6 / metabolism
  • Histone Deacetylase Inhibitors* / chemical synthesis
  • Histone Deacetylase Inhibitors* / chemistry
  • Histone Deacetylase Inhibitors* / pharmacology
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / chemistry
  • Isoenzymes / metabolism
  • Thiazolidinediones* / chemical synthesis
  • Thiazolidinediones* / chemistry
  • Thiazolidinediones* / pharmacology

Substances

  • Histone Deacetylase Inhibitors
  • Isoenzymes
  • Thiazolidinediones
  • HDAC6 protein, human
  • Histone Deacetylase 6