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

Nilsson, Jakob LU ; Gidlöf, Ritha LU ; Nielsen, Elsebet Østergaard; Liljefors, Tommy; Nielsen, Mogens and Sterner, Olov LU (2011) In Bioorganic & Medicinal Chemistry 19(1). p.111-121
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Bioorganic & Medicinal Chemistry
volume
19
issue
1
pages
111 - 121
publisher
Elsevier
external identifiers
  • wos:000285724800011
  • pmid:21163663
  • scopus:78650744695
ISSN
0968-0896
DOI
10.1016/j.bmc.2010.11.050
language
English
LU publication?
yes
id
c5c4c6fe-0bfd-48f0-bd8c-40addf361273 (old id 1756250)
date added to LUP
2011-01-11 14:53:11
date last changed
2017-01-01 03:54:33
@article{c5c4c6fe-0bfd-48f0-bd8c-40addf361273,
  abstract     = {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.},
  author       = {Nilsson, Jakob and Gidlöf, Ritha and Nielsen, Elsebet Østergaard and Liljefors, Tommy and Nielsen, Mogens and Sterner, Olov},
  issn         = {0968-0896},
  language     = {eng},
  number       = {1},
  pages        = {111--121},
  publisher    = {Elsevier},
  series       = {Bioorganic & Medicinal Chemistry},
  title        = {Triazoloquinazolinediones as novel high affinity ligands for the benzodiazepine site of GABA(A) receptors.},
  url          = {http://dx.doi.org/10.1016/j.bmc.2010.11.050},
  volume       = {19},
  year         = {2011},
}