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

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

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Chemical Neurobiology Laboratory, Center for Genomic Medicine , Massachusetts General Hospital , 185 Cambridge Street , Boston , Massachusetts 02114 , United States.
Departments of Psychiatry & Neurology , Massachusetts General Hospital & Harvard Medical School , Boston , Massachusetts 02114 , United States.
Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory , Massachusetts Institute of Technology , Cambridge , Massachusetts 02139 , United States.
Center for Systems Biology , Massachusetts General Hospital , 185 Cambridge Street , Boston , Massachusetts 02114 , United States.


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.


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

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