Class I Histone Deacetylase Inhibition by Tianeptinaline Modulates Neuroplasticity and Enhances Memory

ACS Chem Neurosci. 2018 Sep 19;9(9):2262-2273. doi: 10.1021/acschemneuro.8b00116. Epub 2018 Jun 22.


Through epigenetic and other regulatory functions, the histone deacetylase (HDAC) family of enzymes has emerged as a promising therapeutic target for central nervous system and other disorders. Here we report on the synthesis and functional characterization of new HDAC inhibitors based structurally on tianeptine, a drug used primarily to treat major depressive disorder (MDD) that has a poorly understood mechanism of action. Since the chemical structure of tianeptine resembles certain HDAC inhibitors, we profiled the in vitro HDAC inhibitory activity of tianeptine and demonstrated its ability to inhibit the lysine deacetylase activity of a subset of class I HDACs. Consistent with a model of active site Zn2+ chelation by the carboxylic acid present in tianeptine, newly synthesized analogues containing either a hydroxamic acid or ortho-aminoanilide exhibited increased potency and selectivity among the HDAC family. This in vitro potency translated to improved efficacy in a panel of high-content imaging assays designed to assess HDAC target engagement and functional effects on critical pathways involved in neuroplasticity in both primary mouse neurons and, for the first time, human neurons differentiated from pluripotent stem cells. Most notably, tianeptinaline, a class I HDAC-selective analogue of tianeptine, but not tianeptine itself, increased histone acetylation, and enhanced CREB-mediated transcription and the expression of Arc (activity-regulated cytoskeleton-associated protein). Systemic in vivo administration of tianeptinaline to mice confirmed its brain penetration and was found to enhance contextual fear conditioning, a behavioral test of hippocampal-dependent memory. Tianeptinaline and its derivatives provide new pharmacological tools to dissect chromatin-mediated neuroplasticity underlying memory and other epigenetically related processes implicated in health and disease.

Keywords: Arc; CREB; Cognitive enhancer; acetylation; chromatin; epigenetic; histone deacetylases; human stem cells; neuroepigenetics; neuropharmacology; neuroplasticity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Conditioning, Psychological / drug effects*
  • Cyclic AMP Response Element-Binding Protein
  • Cytoskeletal Proteins / drug effects
  • Cytoskeletal Proteins / genetics
  • Epigenesis, Genetic
  • Fear
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases
  • Humans
  • Memory / drug effects*
  • Mice
  • Nerve Tissue Proteins / drug effects
  • Nerve Tissue Proteins / genetics
  • Neuronal Plasticity / drug effects*
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Pluripotent Stem Cells / cytology
  • Thiazepines / pharmacology
  • Transcription, Genetic / drug effects


  • Cyclic AMP Response Element-Binding Protein
  • Cytoskeletal Proteins
  • Histone Deacetylase Inhibitors
  • Nerve Tissue Proteins
  • Thiazepines
  • activity regulated cytoskeletal-associated protein
  • tianeptine
  • Histone Deacetylases