title: 4-quinolone derivatives: high-affinity ligands at the benzodiazepine site of brain GABA A receptors. synthesis, pharmacology, and pharmacophore modeling.
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.
authors.affiliation: Department of Organic Chemistry, Lund University, P.O.B. 124, SE-221 00 Lund, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Lager
authors.forename: Pierre
authors.initials: P
authors.lastname: Andersson
authors.forename: Jakob
authors.initials: J
authors.lastname: Nilsson
authors.forename: Ingrid
authors.initials: I
authors.lastname: Pettersson
authors.forename: Elsebet Østergaard
authors.initials: EØ
authors.lastname: Nielsen
authors.forename: Mogens
authors.initials: M
authors.lastname: Nielsen
authors.forename: Olov
authors.initials: O
authors.lastname: Sterner
authors.forename: Tommy
authors.initials: T
authors.lastname: Liljefors
mesh_terms: D042462:4-Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry*; D001665:Binding Sites; D001921:Brain / Q000187:drug effects*; D002460:Cell Line; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D058787:GABA-A Receptor Antagonists; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D042462:4-Quinolones; D058787:GABA-A Receptor Antagonists; D008024:Ligands; D011743:Pyrimidines; D011963:Receptors, GABA-A; D001569:Benzodiazepines