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4-quinolone derivatives: High-affinity ligands at the benzodiazepine site of brain GABA(A) receptors. synthesis, pharmacology, and pharmacophore modeling

  • Erik Lager
  • P Andersson
  • Jakob Nilsson
  • I Pettersson
  • EO Nielsen
  • M Nielsen
  • Olov Sterner
  • T Liljefors
Publishing year: 2006
Language: English
Pages: 2526-2533
Publication/Series: Journal of Medicinal Chemistry
Volume: 49
Issue: 8
Document type: Journal article
Publisher: American Chemical Society (ACS)

Abstract english

The 3-ethoxycarbonyl-4-quinolone compound I has previously been identified via a database search as an interesting lead compound for ligand binding at the benzodiazepine site of GABA(A) receptors (Kahnberg et al. J. Mol. Graphics Modelling 2004, 23, 253-261). Pharmacophore-guided optimization of this lead compound yielded a number of high-affinity ligands for the benzodiazepine site including compounds 20 and 23-25 displaying sub-nanomolar affinities. A few of the compounds have been tested on the alpha(1)beta(2)gamma(2s) and alpha(3)beta(2)gamma(2s) GABA(A) receptor subtypes, and two of the compounds (5 and 19) display selectivity for alpha(1) versus alpha(3)-containing receptors by a factor of 22 and 27, respectively. This selectivity for alpha(1)beta(2)gamma(2s) is in the same range as that for the well-known alpha(1) subunit selective compound zolpidem.


  • Medicinal Chemistry


  • ISSN: 1520-4804
Olov Sterner
E-mail: olov [dot] sterner [at] science [dot] lu [dot] se


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