Refinement and evaluation of a pharmacophore model for flavone derivatives binding to the benzodiazepine site of the GABA(A) receptor
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/329133
- author
- Kahnberg, Pia LU ; Lager, Erik LU ; Rosenberg, Celia ; Schougaard, Jette ; Camet, Linda ; Sterner, Olov LU ; Ostergaard Nielsen, Elisabet ; Nielsen, Mogens and Liljefors, Tommy
- organization
- publishing date
- 2002
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Medicinal Chemistry
- volume
- 45
- issue
- 19
- pages
- 4188 - 4201
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- wos:000177913500010
- pmid:12213060
- ISSN
- 1520-4804
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Organic chemistry (S/LTH) (011001240)
- id
- 702bfe03-cffd-45e7-bcc6-969cb41c0cb2 (old id 329133)
- date added to LUP
- 2016-04-01 11:43:45
- date last changed
- 2018-11-21 19:59:36
@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 = {{The 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}}, }