Procognitive Potential of Neuroprotective Triazine 5-HT<sub>6</sub> Receptor Antagonists Tested on Chronic Activity In Vivo in Rats: Computer-Aided Insight into the Role of Chalcogen-Differences on the Pharmacological Profile
Among serotonin receptors, the 5-HT<sub>6</sub> subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. This study aimed to extend the body of preclinical research on two naphthyl-derived methylpiperazine-1,3,5-triazine analogues with thioether (<b>WA-22</b>) or Se-ether (<b>PPK-32</b>) linkers, the newly described compounds having high affinity and selectivity for 5-HT<sub>6</sub> receptors and drug-like parameters in vitro. Thus, crystallography-supported deeper insight into their chemical properties, the comparison of their neuroprotective and pharmacokinetic profiles, and especially their impact on memory disturbances after chronic administration to rats were investigated. As a result, the chronic administration of <b>WA-22</b> completely reversed <b>(+)MK-801</b>-induced memory disturbances evaluated in the novel object recognition test (NORT) in rats. The pharmacokinetic and biochemical results support the notion that this 1,3,5-triazine 5-HT<sub>6</sub> receptor ligand could offer a promising therapeutic tool in CNS-related disorders. The selenium compound <b>PPK-32</b>, with a similar range of activity at acute administration, has shown even broader neuroprotective profiles, especially at the genetic level. However, for therapeutic use, its weaker pharmacokinetics (stability), which is a probable limit for action upon chronic administration, would require improvement, e.g., by an appropriate formulation.
Authors
- Jarosław Handzlik (ORCID: https://orcid.org/0000-0002-1517-4738)
- Joanna Gdula‐Argasińska (ORCID: https://orcid.org/0000-0003-3501-8350)
- Ewelina Honkisz-Orzechowska
- Katarzyna Kucwaj‐Brysz (ORCID: https://orcid.org/0000-0003-4408-9804)
- Natalia Wilczyńska-Zawal
- Agnieszka Cios (ORCID: https://orcid.org/0000-0003-1743-350X)
- Kinga Czarnota-Łydka
- Clemens Zwergel (ORCID: https://orcid.org/0000-0002-3097-0003)
- Ewa Szymańska (ORCID: https://orcid.org/0000-0003-3025-7002)
- Magdalena Jastrzębska‐Więsek
- Alicja Skórkowska (ORCID: https://orcid.org/0000-0002-1167-7610)
- Małgorzata Starek (ORCID: https://orcid.org/0000-0003-0637-0611)
- Barbara Mordyl (ORCID: https://orcid.org/0000-0001-7906-0353)
- Marius Hittinger (ORCID: https://orcid.org/0000-0003-2018-7688)
- Anna Wesołowska (ORCID: https://orcid.org/0000-0003-2383-3278)
- Tadeusz P. Karcz (ORCID: https://orcid.org/0000-0003-4035-659X)
- Anna Partyka (ORCID: https://orcid.org/0000-0001-9606-5228)
- Ewa Żesławska (ORCID: https://orcid.org/0000-0003-1946-9370)
- Sabrina Garbo (ORCID: https://orcid.org/0000-0001-7192-0013)
- Jadwiga Handzlik (ORCID: https://orcid.org/0000-0002-3674-3581)
- Cecilia Battistelli (ORCID: https://orcid.org/0000-0002-5611-7377)
- Wojciech Nitek (ORCID: https://orcid.org/0000-0002-0276-9003)
- Patryk Pyka
- Monika Głuch‐Lutwin (ORCID: https://orcid.org/0000-0003-1632-6569)
- Monika Dąbrowska
- Alessia Raucci (ORCID: https://orcid.org/0000-0003-4182-4420)
Institutions
- Jagiellonian University (PL)
- Cracow University of Technology (PL)
- Sapienza University of Rome (IT)
- Saarland University (DE)
Publication Details
- Journal
- ACS Chemical Neuroscience
- Published
- 2025-02-28
- DOI
- https://doi.org/10.1021/acschemneuro.4c00873
- Citations
- 2
- Primary Topic
- Synthesis and Characterization of Heterocyclic Compounds
- Type
- article
- Field-Weighted Citation Impact
- 1.87
Funders
- Ministero della Salute
- Narodowym Centrum Nauki
- Infrastruktura PL-Grid
- Academic Computer Centre Cyfronet, AGH University of Science and Technology