2. Academic Validation
  3. Phenoxytacrine derivatives: Low-toxicity neuroprotectants exerting affinity to ifenprodil-binding site and cholinesterase inhibition

Phenoxytacrine derivatives: Low-toxicity neuroprotectants exerting affinity to ifenprodil-binding site and cholinesterase inhibition

  • Eur J Med Chem. 2024 Jan 7:266:116130. doi: 10.1016/j.ejmech.2024.116130.
Anna Misiachna 1,  Barbora Svobodova 2,  Jakub Netolicky 3,  Marketa Chvojkova 4,  Lenka Kleteckova 4,  Lukas Prchal 5,  Martin Novak 5,  Martina Hrabinova 2,  Tomas Kucera 6,  Lubica Muckova 2,  Zuzana Moravcova 7,  Jana Zdarova Karasova 2,  Jaroslav Pejchal 5,  Filip Blazek 8,  David Malinak 8,  Kristina Hakenova 9,  Barbora Hrcka Krausova 3,  Marharyta Kolcheva 3,  Marek Ladislav 3,  Jan Korabecny 2,  Jens Pahnke 10,  Karel Vales 9,  Martin Horak 11,  Ondrej Soukup 12
Affiliations

Affiliations

  • 1 Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 20, Prague, Czech Republic; Department of Physiology, Faculty of Science, Charles University in Prague, Albertov 6, 128 43, Prague, Czech Republic.
  • 2 Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Military Faculty of Medicine, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
  • 3 Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 20, Prague, Czech Republic.
  • 4 National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic.
  • 5 Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic.
  • 6 Department of Toxicology and Military Pharmacy, Military Faculty of Medicine, University of Defence, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
  • 7 Faculty of Pharmacy in Hradec Králové, Charles University, Akademika, Heyrovskeho 1203, 50005, Hradec Králové, Czech Republic.
  • 8 Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic.
  • 9 National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic; Third Faculty of Medicine, Charles University, Ruska 87, 100 00, Prague 10, Czech Republic.
  • 10 Department of Neuro-/Pathology, University of Oslo & Oslo University Hospital, Oslo, Norway.
  • 11 Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 20, Prague, Czech Republic. Electronic address: [email protected].
  • 12 Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05, Hradec Kralove, Czech Republic. Electronic address: [email protected].
PMID: 38218127 DOI: 10.1016/j.ejmech.2024.116130
Abstract

Tacrine (THA), a long withdrawn drug, is still a popular scaffold used in medicinal chemistry, mainly for its good reactivity and multi-targeted effect. However, THA-associated hepatotoxicity is still an issue and must be considered in drug discovery based on the THA scaffold. Following our previously identified hit compound 7-phenoxytacrine (7-PhO-THA), we systematically explored the chemical space with 30 novel derivatives, with a focus on low hepatotoxicity, anticholinesterase action, and antagonism at the GluN1/GluN2B subtype of the NMDA receptor. Applying the down-selection process based on in vitro and in vivo pharmacokinetic data, two candidates, I-52 and II-52, selective GluN1/GluN2B inhibitors thanks to the interaction with the ifenprodil-binding site, have entered in vivo pharmacodynamic studies. Finally, compound I-52, showing only minor affinity to AChE, was identified as a lead candidate with favorable behavioral and neuroprotective effects using open-field and prepulse inhibition tests, along with scopolamine-based behavioral and NMDA-induced hippocampal lesion models. Our data show that compound I-52 exhibits low toxicity often associated with NMDA receptor ligands, and low hepatotoxicity, often related to THA-based compounds.

Keywords

Acetylcholinesterase; Alzheimer's disease; Electrophysiology; Glutamate receptor; In vivo; Neuroprotection; Tacrine.

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