2. Academic Validation
  3. An exit beyond the pharmacophore model for 5-HT6R agents - a new strategy to gain dual 5-HT6/5-HT2A action for triazine derivatives with procognitive potential

An exit beyond the pharmacophore model for 5-HT6R agents - a new strategy to gain dual 5-HT6/5-HT2A action for triazine derivatives with procognitive potential

  • Bioorg Chem. 2022 Apr;121:105695. doi: 10.1016/j.bioorg.2022.105695.
Katarzyna Kucwaj-Brysz 1,  Wesam Ali 2,  Rafał Kurczab 3,  Sylwia Sudoł-Tałaj 1,  Natalia Wilczyńska-Zawal 4,  Magdalena Jastrzębska-Więsek 4,  Grzegorz Satała 3,  Barbara Mordyl 5,  Ewa Żesławska 6,  Agnieszka-Olejarz-Maciej 1,  Kinga Czarnota 1,  Gniewomir Latacz 1,  Anna Partyka 4,  Anna Wesołowska 4,  Wojciech Nitek 7,  Jadwiga Handzlik 8
Affiliations

Affiliations

  • 1 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
  • 2 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Kraków, Poland; Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, Campus B 2.1, D-66123 Saarbruecken, Germany.
  • 3 Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland.
  • 4 Department of Clinical Pharmacy, Faculty of Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
  • 5 Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Kraków, Poland.
  • 6 Institute of Biology, Pedagogical University of Krakow, Podchorążych 2, PL 30-084 Kraków, Poland.
  • 7 Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, PL 30-387 Kraków, Poland.
  • 8 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Kraków, Poland. Electronic address: j.handzlik@uj.edu.pl.
PMID: 35228010 DOI: 10.1016/j.bioorg.2022.105695
Abstract

This research allowed us to find the first highly potent 5-HT6/5-HT2A receptor (5-HT6/5-HT2AR) dual antagonists in a group of 1,3,5-triazine compounds as a result of an exit beyond the hydrophobic feature of the pharmacophore model for 5-HT6R antagonists. Design and synthesis of the series (2-16) of new O- and S-containing ether derivatives of 1,3,5-triazines with the double-ring aromatic region have been performed. The new compounds were examined within the comprehensive pharmacological screening, including: radioligand binding assays, functional and ADMET studies in vitro as well as behavioral tests in rats. Crystallographic aspects and computer-aided structure-activity relationship were analyzed, as well. The comprehensive approach led to selection of compound 12 (4-(4-methylpiperazin-1-yl)-6-(2-(naphthalen-2-ylthio)propan-2-yl)-1,3,5-triazin-2-amine) with the most significant dual 5-HT6/5-HT2AR antagonistic action (5-HT6R Ki = 11 nM, 5-HT2AR Ki = 39 nM). Moreover, the compound 12 has satisfactory ADMETox properties in vitro, i.e.: the high permeability through biological membranes, high metabolic stability, neither mutagenic nor hepatotoxic effects, and moderate ability to inhibit CYP3A4. Above all, 12 showed ability to reverse the pharmacologically-induced (MK-801) memory impairment at low doses (1-3 mg/kg) in Novel Object Recognition (NOR) test in rats. Our results indicate a promising potency of dual 5-HT6/5-HT2AR antagonism in the search for novel strategy to fight Alzheimer's disease, which remains an unmet clinical need.

Keywords

1,3,5-triazine; 5-HT(2A) antagonist; 5-HT(6) antagonist; Alzheimer’s disease; NOR; Procognitive activity; Serotonin receptors.

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