Interaction of novel condensed triazine derivatives with central and peripheral type benzodiazepine receptors: synthesis, in vitro pharmacology and modelling

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Abstract

Structurally related sets of triazino-quinoline, triazino-isoquinoline and pyrido-triazine derivatives were synthesised and their binding interactions with central (CBR)- and peripheral-type (PBR) benzodiazepine binding sites have been characterised. Of 33 compounds tested, a new compound, 2-(4-methylphenyl)-3H- [1,2,4] triazino [2, 3-a] quinolin-3-one (1 g) showed the lowest CBR binding inhibition constant (Ki = 42 ± 9 nM) and the highest CBR over PBR selectivity (> 1300). All but the 4-methylphenyl (1 g) structural modifications decreased the affinity and selectivity of the parent compound, 2-phenyl-3H- [1,2,4]triazino[2,3-a]quinolin-3-one (1d) (Ki = 69 ± 9 nM, selectivity > 890). Molecular interactions between selected ligands (standards and triazine derivatives) and α1γ2 subunit-interface residues in a GABAA receptor extracellular domain homology model have been calculated. Comparing data with calculations confirmed hydrogen bonding to γ2Thr142 and hydrophobic interaction with α1His101 as being essential for high-affinity CBR binding.

Original languageEnglish
Pages (from-to)445-456
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume41
Issue number4
DOIs
Publication statusPublished - Apr 2006

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Triazines
GABA-A Receptors
Pharmacology
Derivatives
Molecular interactions
Hydrogen Bonding
Benzodiazepines
Hydrophobic and Hydrophilic Interactions
Hydrogen bonds
Binding Sites
Ligands
isoquinoline
quinoline

Keywords

  • [H]-flunitrazepam binding
  • [H]-PK 11195 binding
  • Condensed triazine derivatives
  • Cyclocondensation
  • Ring closure

ASJC Scopus subject areas

  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

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title = "Interaction of novel condensed triazine derivatives with central and peripheral type benzodiazepine receptors: synthesis, in vitro pharmacology and modelling",
abstract = "Structurally related sets of triazino-quinoline, triazino-isoquinoline and pyrido-triazine derivatives were synthesised and their binding interactions with central (CBR)- and peripheral-type (PBR) benzodiazepine binding sites have been characterised. Of 33 compounds tested, a new compound, 2-(4-methylphenyl)-3H- [1,2,4] triazino [2, 3-a] quinolin-3-one (1 g) showed the lowest CBR binding inhibition constant (Ki = 42 ± 9 nM) and the highest CBR over PBR selectivity (> 1300). All but the 4-methylphenyl (1 g) structural modifications decreased the affinity and selectivity of the parent compound, 2-phenyl-3H- [1,2,4]triazino[2,3-a]quinolin-3-one (1d) (Ki = 69 ± 9 nM, selectivity > 890). Molecular interactions between selected ligands (standards and triazine derivatives) and α1γ2 subunit-interface residues in a GABAA receptor extracellular domain homology model have been calculated. Comparing data with calculations confirmed hydrogen bonding to γ2Thr142 and hydrophobic interaction with α1His101 as being essential for high-affinity CBR binding.",
keywords = "[H]-flunitrazepam binding, [H]-PK 11195 binding, Condensed triazine derivatives, Cyclocondensation, Ring closure",
author = "E. Sz{\'a}rics and Z. Riedl and L. Nyikos and G. Haj{\'o}s and J. Kardos",
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T1 - Interaction of novel condensed triazine derivatives with central and peripheral type benzodiazepine receptors

T2 - synthesis, in vitro pharmacology and modelling

AU - Szárics, E.

AU - Riedl, Z.

AU - Nyikos, L.

AU - Hajós, G.

AU - Kardos, J.

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