Refinement and Evaluation of a Pharmacophore Model for Flavone Derivatives Binding to the Benzodiazepine Site of the GABAA Receptor
- 9 August 2002
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 45 (19), 4188-4201
- https://doi.org/10.1021/jm020839k
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 GABAA 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 3‘-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 (Ki = 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.Keywords
This publication has 15 references indexed in Scilit:
- On the Meaning of Affinity: Cluster Glycoside Effects and Concanavalin AJournal of the American Chemical Society, 1999
- Structure−Activity Relationships and Molecular Modeling Analysis of Flavonoids Binding to the Benzodiazepine Site of the Rat Brain GABAA Receptor ComplexJournal of Medicinal Chemistry, 1999
- 6-Methyl-3′-bromoflavone, a High-Affinity Ligand for the Benzodiazepine Binding Site of the GABAA Receptor with Some Antagonistic PropertiesBiochemical and Biophysical Research Communications, 1999
- Anxioselective properties of 6,3′-dinitroflavone, a high-affinity benzodiazepine receptor ligandEuropean Journal of Pharmacology, 1996
- 6,3'-Dinitroflavone, a novel high affinity ligand for the benzodiazepine receptor with potent anxiolytic propertiesBioorganic & Medicinal Chemistry Letters, 1995
- The rapidly expanding range of neuronal benzodiazepine receptor ligandsProgress in Neurobiology, 1993
- Distribution of GABAA and GABAB receptors in mammalian brain: Potential targets for drug developmentDrug Development Research, 1990
- Diels‐Alder‐Reaktionen mit 2 H ‐Pyran‐2‐onen: Reaktivität und SelektivitätEuropean Journal of Inorganic Chemistry, 1987
- Phase-transfer-catalyzed methylation of hydroxyaromatic acids, hydroxyaromatic aldehydes, and aromatic polycarboxylic acidsEnvironmental Science & Technology, 1985
- Localizing 3H-GABA in Nerve Terminals of Rat Cerebral Cortex by Electron Microscopic AutoradiographyNature, 1971