4-Quinolone Derivatives: High-Affinity Ligands at the Benzodiazepine Site of Brain GABAA Receptors. Synthesis, Pharmacology, and Pharmacophore Modeling
| Autor: | Elsebet Ø. Nielsen, Erik Lager, Pierre Andersson, Ingrid Pettersson, Jakob Nilsson, Olov Sterner, M. Nielsen, Tommy Liljefors |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular Zolpidem Stereochemistry Drug Evaluation Preclinical Alpha (ethology) In Vitro Techniques Ligands Cell Line Benzodiazepines Structure-Activity Relationship chemistry.chemical_compound Drug Discovery medicine Animals Humans Computer Simulation GABA-A Receptor Antagonists Binding site Receptor 4-Quinolones Binding Sites Molecular Structure GABAA receptor Brain Receptors GABA-A Ligand (biochemistry) Rats Pyrimidines chemistry Molecular Medicine Pharmacophore Lead compound medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 49:2526-2533 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm058057p |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|