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.

In: Bioorganic Chemistry, Vol. 40, 02.2012, p. 125-130.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Nilsson, J, Nielsen, EØ, Liljefors, T, Nielsen, MPC & Sterner, O 2012, '3-Alkyl- and 3-amido-isothiazoloquinolin-4-ones as ligands for the benzodiazepine site of GABAA receptors', Bioorganic Chemistry, vol. 40, pp. 125-130. https://doi.org/10.1016/j.bioorg.2011.10.001

APA

Nilsson, J., Nielsen, E. Ø., Liljefors, T., Nielsen, M. P. C., & Sterner, O. (2012). 3-Alkyl- and 3-amido-isothiazoloquinolin-4-ones as ligands for the benzodiazepine site of GABAA receptors. Bioorganic Chemistry, 40, 125-130. https://doi.org/10.1016/j.bioorg.2011.10.001

Vancouver

Nilsson J, Nielsen EØ, Liljefors T, Nielsen MPC, Sterner O. 3-Alkyl- and 3-amido-isothiazoloquinolin-4-ones as ligands for the benzodiazepine site of GABAA receptors. Bioorganic Chemistry. 2012 Feb;40:125-130. https://doi.org/10.1016/j.bioorg.2011.10.001

Author

Nilsson, Jakob ; Nielsen, Elsebet Østergaard ; Liljefors, Tommy ; Nielsen, Mogens Peter Cherly ; Sterner, Olov. / 3-Alkyl- and 3-amido-isothiazoloquinolin-4-ones as ligands for the benzodiazepine site of GABAA receptors. In: Bioorganic Chemistry. 2012 ; Vol. 40. pp. 125-130.

Bibtex

@article{b336312962bb462db35016b03d4abe92,
title = "3-Alkyl- and 3-amido-isothiazoloquinolin-4-ones as ligands for the benzodiazepine site of GABAA 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 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.",
keywords = "Former Faculty of Pharmaceutical Sciences",
author = "Jakob Nilsson and Nielsen, {Elsebet {\O}stergaard} and Tommy Liljefors and Nielsen, {Mogens Peter Cherly} and Olov Sterner",
note = "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",
year = "2012",
month = "2",
doi = "10.1016/j.bioorg.2011.10.001",
language = "English",
volume = "40",
pages = "125--130",
journal = "Bioorganic Chemistry",
issn = "0045-2068",
publisher = "Academic Press",

}

RIS

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