Triazoloquinazolinediones as novel high affinity ligands for the benzodiazepine site of GABA(A) receptors
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Triazoloquinazolinediones as novel high affinity ligands for the benzodiazepine site of GABA(A) receptors. / Nilsson, Jakob; Gidlöf, Ritha; Nielsen, Elsebet Østergaard; Liljefors, Tommy; Nielsen, Mogens Peter Cherly; Sterner, Olov.
I: Bioorganic & Medicinal Chemistry, Bind 19, Nr. 1, 01.01.2011, s. 111-121.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Triazoloquinazolinediones as novel high affinity ligands for the benzodiazepine site of GABA(A) receptors
AU - Nilsson, Jakob
AU - Gidlöf, Ritha
AU - Nielsen, Elsebet Østergaard
AU - Liljefors, Tommy
AU - Nielsen, Mogens Peter Cherly
AU - Sterner, Olov
N1 - 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
PY - 2011/1/1
Y1 - 2011/1/1
N2 - 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.
AB - 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.
KW - Animals
KW - Benzodiazepines
KW - Ligands
KW - Magnetic Resonance Spectroscopy
KW - Models, Molecular
KW - Protein Binding
KW - Quinazolines
KW - Rats
KW - Receptors, GABA-A
KW - Spectrometry, Mass, Electrospray Ionization
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.1016/j.bmc.2010.11.050
DO - 10.1016/j.bmc.2010.11.050
M3 - Journal article
C2 - 21163663
VL - 19
SP - 111
EP - 121
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
SN - 0968-0896
IS - 1
ER -
ID: 35378899