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

Summary, in English

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.

• Författare: Jakob Nilsson; Ritha Gidlöf; Elsebet Østergaard Nielsen; Tommy Liljefors; Mogens Nielsen; Olov Sterner
• Avdelning/ar: Centrum för analys och syntes
• Publiceringsår: 2011
• Språk: Engelska
• Sidor: 111-121
• Publikation/Tidskrift/Serie: Bioorganic & Medicinal Chemistry
• Volym: 19
• Issue: 1
• Länkar: http://dx.doi.org/10.1016/j.bmc.2010.11.050
• Dokumenttyp: Artikel i tidskrift
• Förlag: Elsevier
• Ämne: Organic Chemistry
• Status: Published
• ISBN/ISSN/Övrigt: ISSN: 0968-0896