title: 3-Alkyl- and 3-amido-isothiazoloquinolin-4-ones as ligands for the benzodiazepine site of GABA(A) receptors.
abstract: Based on a pharmacophore model of the benzodiazepine binding site of the GABA(A) receptors, developed with synthetic flavones and potent 3-carbonylquinolin-4-ones, 3-alkyl- and 3-amido-6-methylisothiazoloquinolin-4-ones were designed, prepared and assayed. The suggestion that the interaction between the hydrogen bond donor site H1 with the 3-carbonyl oxygen in 3-carbonylquinolin-4-ones can be replaced by an interaction between H1 and N-2 in the isothiazoloquinolin-4-ones, was confirmed. As with the 3-carbonylquinolin-4-ones, the length of the chain in position 3 is critical for an efficient interaction with the lipophilic pockets of the pharmacophore model. The most potent 3-alkyl derivative, 3-pentyl-6-methylisothiazoloquinolin-4-one, has an affinity (K(i) value) for the benzodiazepine binding site of the GABA(A) receptors of 13 nM. However, by replacing the 3-pentyl with a 3-butyramido group an even more potent compound was obtained, with a K(i) value of 2.8 nM, indicating that the amide function facilitates additional interactions with the binding site.
authors: Division of Organic Chemistry, Lund University, PO Box 124, SE-221 00 Lund, Sweden.
authors: Jakob
authors: J
authors: Nilsson
authors: NeuroSearch A/S, DK-2750 Ballerup, Denmark.
authors: Elsebet
authors: E
authors: Østergaard Nielsen
authors: University of Copenhagen, Faculty of Pharmaceutical Sciences, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
authors: Tommy
authors: T
authors: Liljefors
authors: University of Copenhagen, Faculty of Pharmaceutical Sciences, 2 Universitetsparken, DK-2100 Copenhagen, Denmark.
authors: Mogens
authors: M
authors: Nielsen
authors: Division of Organic Chemistry, Lund University, PO Box 124, SE-221 00 Lund, Sweden. Electronic address: Olov.Sterner@organic.lu.se.
authors: Olov
authors: O
authors: Sterner
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry*; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D006860:Hydrogen Bonding; D008024:Ligands; D054837:Quinolizidines / Q000138:chemical synthesis / Q000737:chemistry*; D051381:Rats; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D054837:Quinolizidines; D011963:Receptors, GABA-A; D001569:Benzodiazepines