title: Triazoloquinazolinediones as novel high affinity ligands for the benzodiazepine site of GABA(A) receptors.
abstract: Based on a pharmacophore model of the benzodiazepine-binding site of GABA(A) receptors, a series of 2-aryl-2,6-dihydro[1,2,4]triazolo[4,3-c]quinazoline-3,5-diones (structure type I) were designed, synthesized, and identified as high-affinity ligands of the binding site. For several compounds, K(i) values of around 0.20nM were determined. They show a structural resemblance with the previously described 2-phenyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones (II) and 2-phenyl-[1,2,4]triazolo[1,5-a]quinoxalin-4(5H)-one (III). The 9-bromo substituted compounds 8a-d were prepared in an 8-step synthesis in an overall yield of approximately 40%, and a library of 9-substituted analogues was prepared by cross-coupling reactions. Compound 8e, 21, 22, and 24 were tested on recombinant rat α(1)β(3)γ(2), α(2)β(3)γ(2), α(3)β(3)γ(2), and α(5)β(3)γ(2) subtypes, and displayed selectivity for the α(1)β(3)γ(2) isoform.
authors.affiliation: Division of Organic Chemistry, Lund University, PO Box 124, SE-221 00 Lund, Sweden.
authors.forename: Jakob
authors.initials: J
authors.lastname: Nilsson
authors.forename: Ritha
authors.initials: R
authors.lastname: Gidlöf
authors.forename: Elsebet Østergaard
authors.initials: EØ
authors.lastname: Nielsen
authors.forename: Tommy
authors.initials: T
authors.lastname: Liljefors
authors.forename: Mogens
authors.initials: M
authors.lastname: Nielsen
authors.forename: Olov
authors.initials: O
authors.lastname: Sterner
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011485:Protein Binding; D011799:Quinazolines / Q000378:metabolism*; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D008024:Ligands; D011799:Quinazolines; D011963:Receptors, GABA-A; D001569:Benzodiazepines