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

J Med Chem. 2006 Apr 20;49(8):2526-33. doi: 10.1021/jm058057p.

Abstract

The 3-ethoxycarbonyl-4-quinolone compound 1 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Quinolones / chemical synthesis*
  • 4-Quinolones / chemistry
  • 4-Quinolones / pharmacology*
  • Animals
  • Benzodiazepines / chemistry*
  • Binding Sites
  • Brain / drug effects*
  • Cell Line
  • Computer Simulation
  • Drug Evaluation, Preclinical
  • GABA-A Receptor Antagonists*
  • Humans
  • In Vitro Techniques
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Rats
  • Receptors, GABA-A / chemistry
  • Structure-Activity Relationship

Substances

  • 4-Quinolones
  • GABA-A Receptor Antagonists
  • Ligands
  • Pyrimidines
  • Receptors, GABA-A
  • Benzodiazepines