Refinement and Evaluation of a Pharmacophore Model for Flavone Derivatives Binding to the Benzodiazepine Site of the GABA_A Receptor

Citations Over TimeTop 17% of 2002 papers

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 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 (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.

Related Papers

• → Novel Approach To Predicting P450-Mediated Drug Metabolism: Development of a Combined Protein and Pharmacophore Model for CYP2D6(1999)160 cited
• → Synthesis, Molecular Modeling Studies, and Pharmacological Activity of Selective A₁Receptor Antagonists(2002)47 cited
• → Pharmacophore-directed Homology Modeling and Molecular Dynamics Simulation of G Protein-coupled Receptor: Study of Possible Binding Modes of 5-HT<sub>2C</sub> Receptor Agonists(2007)12 cited
• → Development of a Pharmacophore Model for Histamine H₃ Receptor Antagonists, Using the Newly Developed Molecular Modeling Program SLATE(2001)40 cited
• Computer-Assisted Determination of Minimum Energy Conformations. 7. A pharmacophore Model of the Active Region of the Alpha2-Adrenoceptor.(1992)