Triazoloquinazolinediones as novel high affinity ligands for the benzodiazepine site of GABA A receptors
Based on a pharmacophore model of the benzodiazepine-binding site of GABAA 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, Ki 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 α1β3γ2, α2β3γ2, α3β3γ2, and α5β3γ2 subtypes, and displayed selectivity for the α1β3γ2 isoform.