Refinement and evaluation of a pharmacophore model for flavone derivatives binding to the benzodiazepine site of the GABA(A) receptor
Author
Summary, in English
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.
Department/s
Publishing year
2002
Language
English
Pages
4188-4201
Publication/Series
Journal of Medicinal Chemistry
Volume
45
Issue
19
Document type
Journal article
Publisher
The American Chemical Society (ACS)
Topic
- Medicinal Chemistry
Status
Published
ISBN/ISSN/Other
- ISSN: 1520-4804