3-Alkyl- and 3-amido-isothiazoloquinolin-4-ones as ligands for the benzodiazepine site of GABAA receptors
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3-Alkyl- and 3-amido-isothiazoloquinolin-4-ones as ligands for the benzodiazepine site of GABAA receptors. / Nilsson, Jakob; Nielsen, Elsebet Østergaard; Liljefors, Tommy; Nielsen, Mogens Peter Cherly; Sterner, Olov.
I: Bioorganic Chemistry, Bind 40, 02.2012, s. 125-130.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - 3-Alkyl- and 3-amido-isothiazoloquinolin-4-ones as ligands for the benzodiazepine site of GABAA receptors
AU - Nilsson, Jakob
AU - Nielsen, Elsebet Østergaard
AU - Liljefors, Tommy
AU - Nielsen, Mogens Peter Cherly
AU - Sterner, Olov
N1 - Keywords: 3-alkyl-6-methylisothiazolo[5,4-b]quinolin-4(9H)-ones; 3-amido-6-methylisothiazolo[5,4-b]quinolin-4(9H)-ones; benzodiazepine binding site; GABA(A) receptors; pharmacophore model
PY - 2012/2
Y1 - 2012/2
N2 - 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 13nM. However, by replacing the 3-pentyl with a 3-butyramido group an even more potent compound was obtained, with a K(i) value of 2.8nM, indicating that the amide function facilitates additional interactions with the binding site.
AB - 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 13nM. However, by replacing the 3-pentyl with a 3-butyramido group an even more potent compound was obtained, with a K(i) value of 2.8nM, indicating that the amide function facilitates additional interactions with the binding site.
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.1016/j.bioorg.2011.10.001
DO - 10.1016/j.bioorg.2011.10.001
M3 - Journal article
C2 - 22055239
VL - 40
SP - 125
EP - 130
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
SN - 0045-2068
ER -
ID: 35379099