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

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.

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