Phenoxytacrine derivatives: Low-toxicity neuroprotectants exerting affinity to ifenprodil-binding site and cholinesterase inhibition
Authors/Creators
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Misiachna, Anna
(Researcher)1, 2
- Svobodova, Barbora (Researcher)3
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Netolicky, Jakub
(Researcher)1
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Chvojkova, Marketa
(Researcher)
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Kleteckova, Lenka
(Researcher)4
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Prchal, Lukas
(Researcher)3
- Novak, Martin (Researcher)3
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Hrabinova, Martina
(Researcher)3, 5
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Kucera, Tomas
(Researcher)5
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Muckova, Lubica
(Researcher)3, 5
- et al. Show all 24 authors
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Misiachna, Anna
(Researcher)1, 2
- Svobodova, Barbora (Researcher)3
-
Netolicky, Jakub
(Researcher)1
-
Chvojkova, Marketa
(Researcher)
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Kleteckova, Lenka
(Researcher)4
-
Prchal, Lukas
(Researcher)3
- Novak, Martin (Researcher)3
-
Hrabinova, Martina
(Researcher)3, 5
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Kucera, Tomas
(Researcher)5
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Muckova, Lubica
(Researcher)3, 5
- Moravcova, Zuzana (Researcher)6
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Zdarova Karasova, Jana
(Researcher)3, 5
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Pejchal, Jaroslav
(Researcher)3
- Blazek, Filip (Researcher)7
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Malinak, David
(Researcher)7
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Hakenova, Kristina
(Researcher)4, 8
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Hrcka Krausova, Barbora
(Researcher)1
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Kolcheva, Marharyta
(Researcher)1
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Ladislav, Marek
(Researcher)1
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Korabecny, Jan
(Researcher)3, 5
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Pahnke, Jens
(Researcher)9
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Vales, Karel
(Researcher)4, 8
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Horak, Martin
(Contact person)1
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Soukup, Ondrej
(Contact person)3
- 1. Institute of Experimental Medicine of the Czech Academy of Sciences
- 2. Department of Physiology, Faculty of Science, Charles University in Prague
- 3. Biomedical Research Center, University Hospital Hradec Kralove
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4.
National Institute of Mental Health
- 5. Department of Toxicology and Military Pharmacy, Military Faculty of Medicine, University of Defence
- 6. Faculty of Pharmacy in Hradec Kralove, Charles University
- 7. Department of Chemistry, Faculty of Science, University of Hradec Kralove
- 8. Third Faculty of Medicine, Charles University
- 9. Department of Neuro-/Pathology, University of Oslo & Oslo University Hospital
Description
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.
Files
Fig1_Compounds_II-52_and_I-52_inhibit_the_hGluN1hGluN2B_receptors.tif
Files
(226.7 MB)
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Additional details
Related works
- Is described by
- Preprint: https://zenodo.org/records/10702874 (Other)
- Is published in
- Journal article: https://zenodo.org/records/10614090 (Other)
Dates
- Available
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2024-04-09