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

• Published in: European journal of medicinal chemistry Vol. 41; no. 4; pp. 445 - 456
• Main Authors: Szárics, Éva, Riedl, Zsuzsanna, Nyikos, Lajos, Hajós, György, Kardos, Julianna
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.04.2006; Elsevier
• Subjects: [ 3H]-flunitrazepam binding; [ 3H]-PK 11195 binding; Animals; Binding, Competitive - drug effects; Biological and medical sciences; Central Nervous System - drug effects; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Chemistry, Medicinal; Chromatography, Thin Layer; Condensed triazine derivatives; Cyclocondensation; Flunitrazepam - pharmacokinetics; GABA Modulators - pharmacokinetics; Gabaergic and benzodiazepinic system; In Vitro Techniques; Isoquinolines - pharmacokinetics; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Male; Medical sciences; Models, Molecular; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peripheral Nervous System - drug effects; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Point Mutation; Prosencephalon - drug effects; Prosencephalon - metabolism; Rats; Rats, Wistar; Receptors, GABA-A - chemistry; Receptors, GABA-A - drug effects; Receptors, GABA-A - genetics; Ring closure; Science & Technology; Spectrophotometry, Infrared; Structure-Activity Relationship; Synaptic Membranes - drug effects; Synaptic Membranes - metabolism; Triazines - chemical synthesis; Triazines - pharmacology; PBR; [ 3H]-PK 11195 binding; LRAA; Ro 5-4864; Cyclocondensation; [ 3H]-flunitrazepam binding; Condensed triazine derivatives; TRIS; Ro15-1788 (flumazenil); CBR; Ring closure; K i,FLU; K i,PK; PK 11195; Flunitrazepam; POINT MUTATION; ALPHA-SUBUNIT; [H-3]-PK 11195 binding; ring closure; cyclocondensation; AMINO-ACID; SELECTIVE LIGANDS; GABA(A) RECEPTOR; A RECEPTOR; STRUCTURAL REQUIREMENTS; [H-3]-flunitrazepam binding; AMINOBUTYRIC ACID(A) RECEPTOR; GAMMA SUBUNIT; BINDING-SITE; condensed triazine derivatives; [3H]-PK 11195 binding; [3H]-flunitrazepam binding; Tritium; Pharmacology; Benzodiazepine receptor; Hydrogen Isotopes; In vitro; Modeling; Cyclization; Structure activity relation; Molecular model; Chemical synthesis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2005.10.015

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)-3 H- [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-3 H- [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 α 1γ 2 subunit-interface residues in a GABA A receptor extracellular domain homology model have been calculated. Comparing data with calculations confirmed hydrogen bonding to γ 2Thr142 and hydrophobic interaction with α 1His101 as being essential for high-affinity CBR binding.