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 (K(i) = 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) (K(i) = 69 +/- 9 nM, selectivity >890). Molecular interactions between selected ligands (standards and triazine derivatives) and alpha(1)gamma(2) subunit-interface residues in a GABA(A) receptor extracellular domain homology model have been calculated. Comparing data with calculations confirmed hydrogen bonding to gamma(2)Thr142 and hydrophobic interaction with alpha(1)His101 as being essential for high-affinity CBR binding.