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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Kahnberg P,Lager E,Rosenberg C,Schougaard J,Camet L,Sterner O,Østergaard Nielsen E,Nielsen M,Liljefors T

doi

10.1021/jm020839k

keywords:

subject

Has Abstract

pub_date

2002-09-12 00:00:00

pages

4188-201

issue

19

eissn

0022-2623

issn

1520-4804

pii

jm020839k

journal_volume

45

pub_type

杂志文章

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