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Updated: Sep 10, 2025

Simultaneous Measurement of HDAC1 and HDAC6 Activity in HeLa Cells Using UHPLC-MS
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Intepirdine Derivatives Possessing Dual 5HT6 Antagonism / HDAC6 Inhibitory Activity.

Andreas Gkanas1, Maria Koutiva1, Theodora Katsila2

  • 1Department of Chemistry, University of Patras, Rio Campus, Achaia, 26504, Greece.

Chemistry (Weinheim an Der Bergstrasse, Germany)
|August 22, 2025
PubMed
Summary
This summary is machine-generated.

Researchers developed a novel dual-acting drug targeting both 5-HT6 receptors and HDAC6 enzymes. This compound shows potential for enhancing cognitive function in conditions like Alzheimer's disease.

Keywords:
5HT6 antagonistsAlzheimer DiseaseBuchwald‐Hartwig N‐arylationHDAC6 inhibitorsT3P amide synthesiscognitive declinedementiahydroxamic acidsintepirdinemulti‐targeting directed ligandsquinoline Ullmann‐type couplingsulfide oxidation to sulfone

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Area of Science:

  • Neuroscience
  • Medicinal Chemistry
  • Pharmacology

Background:

  • Alzheimer's Disease (AD) and other dementias significantly impact quality of life, with limited effective treatments available.
  • Current drugs primarily manage symptoms, while targeted therapies have faced clinical trial failures.
  • Multitargeting ligands offer a promising strategy for complex neurodegenerative diseases by addressing multiple biological mechanisms.

Purpose of the Study:

  • To design and synthesize novel dual-acting ligands targeting both 5-HT6 receptors and HDAC6 enzymes.
  • To explore the potential of these compounds as cognitive enhancers.
  • To develop a new therapeutic paradigm for neurodegenerative disorders.

Main Methods:

  • Designed and synthesized dual 5-HT6 antagonists / HDAC6 inhibitors by linking aryl-hydroxamic acid pharmacophores to intepirdine.
  • Developed a gram-scale synthesis of intepirdine.
  • Characterized the synthesized derivatives for their inhibitory potency and receptor affinity.

Main Results:

  • Successfully synthesized novel dual-acting 5-HT6 antagonists / HDAC6 inhibitors.
  • Derivative RG-283AG demonstrated sub-micromolar potency against HDAC6 (IC50 = 0.54 μM) and nanomolar affinity for 5-HT6 receptors (Ki = 0.7 nM).
  • RG-283AG exhibited favorable blood-brain barrier penetration capacity.

Conclusions:

  • RG-283AG is the first reported dual-acting 5-HT6 / HDAC6 ligand with potential cognitive-enhancing properties.
  • This dual-targeting approach represents a promising strategy for developing new therapies for Alzheimer's Disease and other dementias.
  • Further investigation into RG-283AG's therapeutic potential is warranted.