Chlorine substituents and linker topology as factors of 5-HT 6 R activity for novel highly active 1,3,5-triazine derivatives with procognitive properties in vivo

In the light of recent lines of evidence, 5-HT R ligands are a promising tool for future treatment of memory impairment. Hence, this study has supplied highly potent 5-HT R agents with procognitive effects, which represent an original chemical class of 1,3,5-triazines, different from widely studied...

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Published in:European journal of medicinal chemistry 2020-10, Vol.203, p.112529
Main Authors: Sudoł, Sylwia, Kucwaj-Brysz, Katarzyna, Kurczab, Rafał, Wilczyńska, Natalia, Jastrzębska-Więsek, Magdalena, Satała, Grzegorz, Latacz, Gniewomir, Głuch-Lutwin, Monika, Mordyl, Barbara, Żesławska, Ewa, Nitek, Wojciech, Partyka, Anna, Buzun, Kamila, Doroz-Płonka, Agata, Wesołowska, Anna, Bielawska, Anna, Handzlik, Jadwiga
Format: Article
Language:English
Subjects:
Animals
Chlorine - chemistry
Cognition - drug effects
Molecular Docking Simulation
Protein Conformation
Rats
Receptors, Serotonin - chemistry
Receptors, Serotonin - metabolism
Safety
Structure-Activity Relationship
Triazines - chemistry
Triazines - metabolism
Triazines - pharmacology
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Summary:In the light of recent lines of evidence, 5-HT R ligands are a promising tool for future treatment of memory impairment. Hence, this study has supplied highly potent 5-HT R agents with procognitive effects, which represent an original chemical class of 1,3,5-triazines, different from widely studied sulfone and indole-like 5-HT R ligands. The new compounds were rationally designed as modifications of lead, 4-(1-(2-chlorophenoxy)ethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (1), involving an introduction of: (i) two chlorines at benzene ring and (ii) varied linkers joining the triazine ring to aromatic ethers. Synthesis, in vitro and in vivo biological tests and computer-aided SAR analysis for 19 new compounds were carried out. Most of the new triazines displayed high affinity (K  
ISSN:1768-3254