2. Academic Validation
  3. Hydrophobicity modulation via the substituents at positions 2 and 4 of 1,3,5-triazine to enhance therapeutic ability against Alzheimer's disease for potent serotonin 5-HT6R agents

Hydrophobicity modulation via the substituents at positions 2 and 4 of 1,3,5-triazine to enhance therapeutic ability against Alzheimer's disease for potent serotonin 5-HT6R agents

  • Eur J Med Chem. 2023 Nov 15;260:115756. doi: 10.1016/j.ejmech.2023.115756.
Sylwia Sudoł-Tałaj 1,  Katarzyna Kucwaj-Brysz 2,  Sabina Podlewska 3,  Rafał Kurczab 3,  Grzegorz Satała 3,  Barbara Mordyl 4,  Monika Głuch-Lutwin 4,  Natalia Wilczyńska-Zawal 5,  Magdalena Jastrzębska-Więsek 5,  Kinga Czarnota-Łydka 1,  Kinga Kurowska 2,  Monika Kubacka 6,  Ewa Żesławska 7,  Wojciech Nitek 8,  Agnieszka Olejarz-Maciej 2,  Agata Doroz-Płonka 2,  Anna Partyka 5,  Gniewomir Latacz 2,  Anna Wesołowska 5,  Jadwiga Handzlik 9
Affiliations

Affiliations

  • 1 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Kraków, Poland; Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, Św. Łazarza 16, PL 31-530, Kraków, Poland.
  • 2 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Kraków, Poland.
  • 3 Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Medicinal Chemistry, Smętna 12, PL 31-343, Kraków, Poland.
  • 4 Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Kraków, Poland.
  • 5 Department of Clinical Pharmacy, Faculty of Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Kraków, Poland.
  • 6 Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Kraków, Poland.
  • 7 Institute of Biology and Earth Sciences, Pedagogical University of Krakow, Podchorążych 2, PL 30-084, Kraków, Poland.
  • 8 Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, PL 30-387, Kraków, Poland.
  • 9 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688, Kraków, Poland. Electronic address: [email protected].
PMID: 37657272 DOI: 10.1016/j.ejmech.2023.115756
Abstract

Alzheimer's disease (AD), a neurodegenerative disorder with a complex aetiology, is the most common memory dysfunction particularly affecting the elderly. Various protein targets have been classified to be involved in the AD treatment, including 5-HT6 receptor (5-HT6R). So far, the 5-HT6R ligands obtained by our research group have become a good basis for hydrophobicity modulation to give a chance for more effective action toward AD by additional influence on target enzymes, e.g. cyclin-dependent kinase 5 (CDK5). In the search for 5-HT6R agents with additional inhibitory action on the Enzyme, a series of 25 new 1,3,5-triazines (7-31) as modifications of lead, 4-[1-(2,5-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-amine (6), was rationally designed. Molecular modelling, synthesis, crystallographic studies, in vitro biological assays and behavioral studies in vivo were performed. The new triazines showed high affinity (Ki < 100 nM) and selectivity for 5-HT6R. The most effective one, 4-[1-(2,5-difluorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-amine (8), exhibited the strong antagonistic action towards 5-HT6R (Ki = 5 nM, pKb = 8.16), had an impact on the memory processes in the Novel Object Recognition test and displayed anxiolytic-like activity in the Elevated Plus Maze test in rats. Moreover, it had the antiplatelet effect as well as very good permeability (PAMPA model), high metabolic stability (RLMs) and satisfactory safety in vitro. Although the CDK5 inhibitory effects in vitro for the tested compounds (8, 10, 14, 18, 26-31) missed the potency expected from in silico simulations, the novel antagonist (8) with a very satisfying pharmacological and ADMET profile can serve as a new lead structure in further searches for innovative therapy against AD with accompanying symptoms.

Keywords

1,3,5-triazine; 5-HT(6) serotonin receptors; molecular modelling.

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