Triazoloquinazolinediones as novel high affinity ligands for the benzodiazepine site of GABA(A) receptors

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Jakob Nilsson, Ritha Gidlöf, Elsebet Østergaard Nielsen, Tommy Liljefors, Mogens Peter Cherly Nielsen, Olov Sterner

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 a(1)ß(3)¿(2), a(2)ß(3)¿(2), a(3)ß(3)¿(2), and a(5)ß(3)¿(2) subtypes, and displayed selectivity for the a(1)ß(3)¿(2) isoform.
Original languageEnglish
JournalBioorganic & Medicinal Chemistry
Volume19
Issue number1
Pages (from-to)111-121
ISSN0968-0896
DOIs
Publication statusPublished - 1 Jan 2011

Bibliographical note

Keywords: 2-aryl-2,6-dihydro[1,2,4]triazolo-[4,3-c]quinazoline-3,5-diones; benzodiazepine binding site; GABA(A) receptors; GABA(A) receptor subtypes; pharmacophore model

    Research areas

  • Animals, Benzodiazepines, Ligands, Magnetic Resonance Spectroscopy, Models, Molecular, Protein Binding, Quinazolines, Rats, Receptors, GABA-A, Spectrometry, Mass, Electrospray Ionization
  • The Faculty of Pharmaceutical Sciences

ID: 35378899