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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Erik Lager
  • Jakob Nilsson
  • Elsebet Østergaard Nielsen
  • Mogens Peter Cherly Nielsen
  • Tommy Liljefors
  • Olov Sterner
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 GABA(A) 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 alpha- and a gamma-subunit in the GABA(A) receptor, selected compounds were tested on the alpha(1)beta(2)gamma(2s), alpha(2)beta(2)gamma(2s) and alpha(3)beta(2)gamma(2s) GABA(A) receptor subtypes. The 3-acyl-4-quinolones display various degrees of selectivity for alpha(1)- versus alpha(2)- and alpha(3)-containing receptors, and high-affinity ligands essentially selective for alpha(1) over alpha(3) were developed.
Original languageEnglish
JournalBioorganic & Medicinal Chemistry
Issue number14
Pages (from-to)6936-6948
Publication statusPublished - 2008

Bibliographical note

Keywords: 4-Quinolones; Animals; Benzodiazepines; Binding Sites; Ligands; Protein Binding; Protein Subunits; Receptors, GABA-A; Structure-Activity Relationship

ID: 10159584