title: Refinement and evaluation of a pharmacophore model for flavone derivatives binding to the benzodiazepine site of the GABA(A) receptor.
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.
authors.affiliation: Department of Organic and Bioorganic Chemistry, Lund University, P.O. Box 124, S-221 00 Lund, Sweden.
authors.forename: Pia
authors.initials: P
authors.lastname: Kahnberg
authors.forename: Erik
authors.initials: E
authors.lastname: Lager
authors.forename: Celia
authors.initials: C
authors.lastname: Rosenberg
authors.forename: Jette
authors.initials: J
authors.lastname: Schougaard
authors.forename: Linda
authors.initials: L
authors.lastname: Camet
authors.forename: Olov
authors.initials: O
authors.lastname: Sterner
authors.forename: Elsebet
authors.initials: E
authors.lastname: Østergaard Nielsen
authors.forename: Mogens
authors.initials: M
authors.lastname: Nielsen
authors.forename: Tommy
authors.initials: T
authors.lastname: Liljefors
mesh_terms: D000818:Animals; D001665:Binding Sites; D002540:Cerebral Cortex / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*
chemical_list: C465769:5'-bromo-2'-hydroxy-6-methylflavone; D005419:Flavonoids; D011963:Receptors, GABA-A