The first-in-class 1,3,5-triazine-derived dual 5-HT6R/FAAH modulators in search for potential drug against neurodegenerative diseases with cognitive impairment

  • Eur J Med Chem. 2025 Nov 15:298:118026. doi: 10.1016/j.ejmech.2025.118026.
Kinga Czarnota-Łydka  1 ,  Katarzyna Kucwaj-Brysz  2 ,  Barbara Mordyl  3 ,  Monika Głuch-Lutwin  4 ,  Tadeusz Karcz  5 ,  Magdalena Jastrzębska-Więsek  6 ,  Anna Partyka  7 ,  Monika Dąbrowska  8 ,  Grzegorz Satała  9 ,  Sylwia Sudoł-Tałaj  10 ,  Leonardo Brunetti  11 ,  Modesto de Candia  12 ,  Rosa Purgatorio  13 ,  Marco Cerini  14 ,  Luca Piemontese  15 ,  Sabina Podlewska  16 ,  Gniewomir Latacz  17 ,  Małgorzata Starek  18 ,  Anna Wesołowska  19 ,  Antonio Carrieri  20 ,  Jadwiga Handzlik  21
Affiliations
  • 1. Chair of Chemical Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland; Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, św. Łazarza 15, 31-530, Cracow, Poland. Electronic address: [email protected].
  • 2. Chair of Chemical Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: [email protected].
  • 3. Department of Pharmacobiology, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: [email protected].
  • 4. Department of Pharmacobiology, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: [email protected].
  • 5. Chair of Chemical Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: [email protected].
  • 6. Department of Clinical Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: [email protected].
  • 7. Department of Clinical Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: [email protected].
  • 8. Department of Inorganic Chemistry and Pharmaceutical Analytics, Jagiellonian University, Medical College, Medyczna 9, 30-688, Kraków, Poland. Electronic address: [email protected].
  • 9. Maj Institute of Pharmacology Polish Academy of Sciences, Department of Medicinal Chemistry, Smętna 12, PL, 31-343, Cracow, Poland. Electronic address: [email protected].
  • 10. Chair of Chemical Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: [email protected].
  • 11. Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: [email protected].
  • 12. Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: [email protected].
  • 13. Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: [email protected].
  • 14. Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: [email protected].
  • 15. Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: [email protected].
  • 16. Maj Institute of Pharmacology Polish Academy of Sciences, Department of Medicinal Chemistry, Smętna 12, PL, 31-343, Cracow, Poland. Electronic address: [email protected].
  • 17. Chair of Chemical Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: [email protected].
  • 18. Department of Inorganic Chemistry and Pharmaceutical Analytics, Jagiellonian University, Medical College, Medyczna 9, 30-688, Kraków, Poland. Electronic address: [email protected].
  • 19. Department of Clinical Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: [email protected].
  • 20. Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: [email protected].
  • 21. Chair of Chemical Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: [email protected].
PMID: 40774068 DOI: 10.1016/j.ejmech.2025.118026
Abstract

Due to complex etiology, a promising approach to find an effective therapy of Alzheimer's disease (AD) lies in the search for multitarget ligands. Within this study, we have identified novel 1,3,5-triazine derivatives that modulate either the serotonin 5-HT6 receptor and the fatty acid amide hydrolase (FAAH) enzyme, also slightly inhibiting acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) Enzymes, thus representing pioneering multitarget approach to address key pathological mechanisms in AD. Among the synthesized compounds, the m-chlorobenzyl- 7 (5-HT6R pKi = 7.59) and the trimethoxybenzyl- 23 (5-HT6R pKi = 6.33) derivatives exhibited the most favorable multitarget action, with 5-HT6R selectivity over Other GPCR off-targets. Comprehensive molecular modeling provided insights into the compounds interactions with the molecular targets considered. In vitro evaluations revealed satisfactory metabolic stability and low risks of toxicity, including neurotoxicity. Notably, 23 demonstrated significant neuroprotective effects against Aβ1-42-induced toxicity in hippocampal model (HT-22). Furthermore, in a Novel Object Recognition (NOR) test, both 7 and 23 ameliorated MK-801-induced memory deficits in rats. The results indicate the therapeutic potential for these first-in-class dual modulators of both, endocannabinoid system and serotonergic neurotransmission, to address neurodegenerative diseases such as AD.

Keywords
1,3,5-triazine; 5-HT(6) serotonin receptors; Alzheimer's disease; FAAH.
Products