2. Academic Validation
  3. 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

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

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: kinga.czarnota@doctoral.uj.edu.pl.
  • 2 Chair of Chemical Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: katarzyna.kucwaj@uj.edu.pl.
  • 3 Department of Pharmacobiology, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: barbara.mordyl@uj.edu.pl.
  • 4 Department of Pharmacobiology, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: monika.gluch-lutwin@uj.edu.pl.
  • 5 Chair of Chemical Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: t.karcz@uj.edu.pl.
  • 6 Department of Clinical Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: m.jastrzebska-wiesek@uj.edu.pl.
  • 7 Department of Clinical Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: annairena.partyka@uj.edu.pl.
  • 8 Department of Inorganic Chemistry and Pharmaceutical Analytics, Jagiellonian University, Medical College, Medyczna 9, 30-688, Kraków, Poland. Electronic address: monika.1.dabrowska@uj.edu.pl.
  • 9 Maj Institute of Pharmacology Polish Academy of Sciences, Department of Medicinal Chemistry, Smętna 12, PL, 31-343, Cracow, Poland. Electronic address: satala@if-pan.krakow.pl.
  • 10 Chair of Chemical Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: sylwia1.sudol@uj.edu.pl.
  • 11 Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: leonardo.brunetti@uniba.it.
  • 12 Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: modesto.decandia@uniba.it.
  • 13 Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: rosa.purgatorio@uniba.it.
  • 14 Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: marco.cerini@uniba.it.
  • 15 Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: luca.piemontese@uniba.it.
  • 16 Maj Institute of Pharmacology Polish Academy of Sciences, Department of Medicinal Chemistry, Smętna 12, PL, 31-343, Cracow, Poland. Electronic address: smusz@if-pan.krakow.pl.
  • 17 Chair of Chemical Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: gniewomir.latacz@uj.edu.pl.
  • 18 Department of Inorganic Chemistry and Pharmaceutical Analytics, Jagiellonian University, Medical College, Medyczna 9, 30-688, Kraków, Poland. Electronic address: m.starek@uj.edu.pl.
  • 19 Department of Clinical Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: a.wesolowska@uj.edu.pl.
  • 20 Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy. Electronic address: antonio.carrieri@uniba.it.
  • 21 Chair of Chemical Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL, 30-688, Cracow, Poland. Electronic address: j.handzlik@uj.edu.pl.
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.

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