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 (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.
authors.affiliation: Department of Neurochemistry, Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences, Budapest.
authors.forename: Eva
authors.initials: E
authors.lastname: Szárics
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Riedl
authors.forename: Lajos
authors.initials: L
authors.lastname: Nyikos
authors.forename: György
authors.initials: G
authors.lastname: Hajós
authors.forename: Julianna
authors.initials: J
authors.lastname: Kardos
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002855:Chromatography, Thin Layer; D005445:Flunitrazepam / Q000493:pharmacokinetics; D018757:GABA Modulators / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000493:pharmacokinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D017933:Peripheral Nervous System / Q000187:drug effects*; D017354:Point Mutation; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D018757:GABA Modulators; D007546:Isoquinolines; D011963:Receptors, GABA-A; D014227:Triazines; D005445:Flunitrazepam; C037850:PK 11195