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Affinity of 3-acyl substituted 4-quinolones at the benzodiazepine site of GABAA receptors.

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Author

  • Erik Lager
  • Jakob Nilsson
  • Elsebet Østergaard Nielsen
  • Mogens Nielsen
  • Tommy Liljefors
  • Olov Sterner

Summary, in English

The finding that alkyl 1,4-dihydro-4-oxoquinoline-3-carboxylate and N-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxamide derivatives may be high-affinity ligands at the benzodiazepine binding site of the GABAA receptor, prompted a study of 3-acyl-1,4-dihydro-4-oxoquinoline (3-acyl-4-quinolones). In general, the affinity of the 3-acyl derivatives was found to be comparable with the 3-carboxylate and the 3-carboxamide derivatives, and certain substituents (e.g., benzyl) in position 6 were again shown to be important. As it is believed that the benzodiazepine binding site is situated between an α- and a γ-subunit in the GABAA receptor, selected compounds were tested on the α1β2γ2s, α2β2γ2s and α3β2γ2s GABAA receptor subtypes. The 3-acyl-4-quinolones display various degrees of selectivity for α1- versus α2- and α3-containing receptors, and high-affinity ligands essentially selective for α1 over α3 were developed.

Publishing year

2008

Language

English

Pages

6936-6948

Publication/Series

Bioorganic & Medicinal Chemistry

Volume

16

Issue

14

Document type

Journal article

Publisher

Elsevier

Topic

  • Organic Chemistry

Keywords

  • 3-Acyl-1
  • 4-dihydro-4-oxoquinolines
  • Benzodiazepine binding site
  • GABAA receptor
  • GABAA receptor subtypes
  • Pharmacophore model

Status

Published

ISBN/ISSN/Other

  • ISSN: 0968-0896