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Refinement and evaluation of a pharmacophore model for flavone derivatives binding to the benzodiazepine site of the GABA(A) receptor

Kahnberg, Pia LU ; Lager, Erik LU ; Rosenberg, Celia; Schougaard, Jette; Camet, Linda; Sterner, Olov LU ; Ostergaard Nielsen, Elisabet; Nielsen, Mogens and Liljefors, Tommy (2002) In Journal of Medicinal Chemistry 45(19). p.4188-4201
Abstract
To further develop and evaluate a pharmacophore model previously proposed by Cook and co-workers (Drug Des. Discovery 1995,12,193-248) for ligands binding to the benzodiazepine site of the GABA(A) receptor, 40 new flavone derivatives have been synthesized and their affinities for the benzodiazepine site have been determined. Two new regions of steric repulsive interactions between ligand and receptor have been characterized, and the receptor region in the vicinity of 6- and 8'-substituents has been mapped out. 2'-Hydroxy substitution is shown to give a significant increase in affinity, which is interpreted in terms of a novel hydrogen bond interaction with the previously proposed hydrogen bond-accepting site A2. On the basis of the results... (More)
To further develop and evaluate a pharmacophore model previously proposed by Cook and co-workers (Drug Des. Discovery 1995,12,193-248) for ligands binding to the benzodiazepine site of the GABA(A) receptor, 40 new flavone derivatives have been synthesized and their affinities for the benzodiazepine site have been determined. Two new regions of steric repulsive interactions between ligand and receptor have been characterized, and the receptor region in the vicinity of 6- and 8'-substituents has been mapped out. 2'-Hydroxy substitution is shown to give a significant increase in affinity, which is interpreted in terms of a novel hydrogen bond interaction with the previously proposed hydrogen bond-accepting site A2. On the basis of the results of these studies and the refined pharmacophore model, 5'-bromo-2'-hydroxy-6-methylflavone, the highest affinity flavone derivative reported so far (K-i = 0.9 nM), was successfully designed. A comparison of the pharmacophore model with a recently proposed alternative model (Marder; et al. Bioorg. Med. Chem., 2001, 9, 323-335) has been made. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
Journal of Medicinal Chemistry
volume
45
issue
19
pages
4188 - 4201
publisher
American Chemical Society (ACS)
external identifiers
  • wos:000177913500010
  • pmid:12213060
ISSN
1520-4804
language
English
LU publication?
yes
id
702bfe03-cffd-45e7-bcc6-969cb41c0cb2 (old id 329133)
date added to LUP
2007-10-31 16:09:27
date last changed
2016-04-15 18:55:24
@article{702bfe03-cffd-45e7-bcc6-969cb41c0cb2,
  abstract     = {To further develop and evaluate a pharmacophore model previously proposed by Cook and co-workers (Drug Des. Discovery 1995,12,193-248) for ligands binding to the benzodiazepine site of the GABA(A) receptor, 40 new flavone derivatives have been synthesized and their affinities for the benzodiazepine site have been determined. Two new regions of steric repulsive interactions between ligand and receptor have been characterized, and the receptor region in the vicinity of 6- and 8'-substituents has been mapped out. 2'-Hydroxy substitution is shown to give a significant increase in affinity, which is interpreted in terms of a novel hydrogen bond interaction with the previously proposed hydrogen bond-accepting site A2. On the basis of the results of these studies and the refined pharmacophore model, 5'-bromo-2'-hydroxy-6-methylflavone, the highest affinity flavone derivative reported so far (K-i = 0.9 nM), was successfully designed. A comparison of the pharmacophore model with a recently proposed alternative model (Marder; et al. Bioorg. Med. Chem., 2001, 9, 323-335) has been made.},
  author       = {Kahnberg, Pia and Lager, Erik and Rosenberg, Celia and Schougaard, Jette and Camet, Linda and Sterner, Olov and Ostergaard Nielsen, Elisabet and Nielsen, Mogens and Liljefors, Tommy},
  issn         = {1520-4804},
  language     = {eng},
  number       = {19},
  pages        = {4188--4201},
  publisher    = {American Chemical Society (ACS)},
  series       = {Journal of Medicinal Chemistry},
  title        = {Refinement and evaluation of a pharmacophore model for flavone derivatives binding to the benzodiazepine site of the GABA(A) receptor},
  volume       = {45},
  year         = {2002},
}