Aminotriazines with indole motif as novel, 5-HT7 receptor ligands with atypical binding mode

  • Bioorg Chem. 2020 Nov;104:104254. doi: 10.1016/j.bioorg.2020.104254.
Damian Kułaga  1 ,  Jolanta Jaśkowska  2 ,  Grzegorz Satała  3 ,  Gniewomir Latacz  4 ,  Paweł Śliwa  2
Affiliations
  • 1. Faculty of Chemical Engineering and Technology, Institute of Organic Chemistry and Technology, Cracow University of Technology, 24 Warszawska Street, 31-155 Kraków, Poland. Electronic address: [email protected].
  • 2. Faculty of Chemical Engineering and Technology, Institute of Organic Chemistry and Technology, Cracow University of Technology, 24 Warszawska Street, 31-155 Kraków, Poland.
  • 3. Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland.
  • 4. Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
PMID: 32919133 DOI: 10.1016/j.bioorg.2020.104254
Abstract

Developing new and selective 5-HT7R ligands may have a key impact on the treatment of central nervous system diseases including depression. We have found that indoleaminotriazine core fused with alkyl aryl moiety exhibits high affinity and selectivity to 5-HT7R. SAR analysis demonstrated that the ethyl or ethoxy group (5c 5-HT7R Ki = 8 nM; 5d 5-HT7R Ki = 55 nM) is the optimal carbon linker between triazine and aryl moiety. The results of the molecular dynamics simulations show stable interaction with E7.34 upon binding to a 5-HT7R. Compounds 5c and 5d were tested for early ADMET parameters. Compounds are not hepatotoxic and exhibit moderate potential interaction with Other drugs metabolized by CYP3A4 or CYP2D6.

Keywords
5-HT(7)R ligands; Docking; Drug design; Medicinal chemistry; Microwave chemistry; Molecular dynamics.
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