Refinement and evaluation of a pharmacophore model for flavone derivatives binding to the benzodiazepine site of the GABA(A) receptor
Research output: Contribution to journal › Article
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.
|Research areas and keywords||
Subject classification (UKÄ) – MANDATORY
|Journal||Journal of Medicinal Chemistry|
|Publication status||Published - 2002|
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)