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Triazoloquinazolinediones as novel high affinity ligands for the benzodiazepine site of GABA(A) receptors |
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| Authors: | Nilsson Jakob Gidlöf Ritha Nielsen Elsebet Østergaard Liljefors Tommy Nielsen Mogens Sterner Olov |
| Institution: | a Division of Organic Chemistry, Lund University, PO Box 124, SE-221 00 Lund, Sweden b NeuroSearch A/S, DK-2750 Ballerup, Denmark c University of Copenhagen, Faculty of Pharmaceutical Sciences, 2 Universitetsparken, DK-2100 Copenhagen, Denmark |
| Abstract: | Based on a pharmacophore model of the benzodiazepine-binding site of GABAA receptors, a series of 2-aryl-2,6-dihydro1,2,4]triazolo4,3-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 0.20 nM were determined. They show a structural resemblance with the previously described 2-phenyl-2H-pyrazolo4,3-c]quinolin-3(5H)-ones (II) and 2-phenyl-1,2,4]triazolo1,5-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 ??1??3??2, ??2??3??2, ??3??3??2, and ??5??3??2 subtypes, and displayed selectivity for the ??1??3??2 isoform. |
| Keywords: | 2-Aryl-2 6-dihydro[1 2 4]triazolo[4 3-c]quinazoline-3 5-diones Benzodiazepine binding site GABAA receptors GABAA receptor subtypes Pharmacophore model |
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