3-Alkyl- and 3-amido-isothiazoloquinolin-4-ones as ligands for the benzodiazepine site of GABA(A) receptors.
(2011) In Bioorganic & Medicinal Chemistry Letters- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/2221123
- author
- Nilsson, Jakob LU ; Ostergaard Nielsen, Elsebet ; Liljefors, Tommy ; Nielsen, Mogens and Sterner, Olov LU
- organization
- publishing date
- 2011-10-17
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Bioorganic & Medicinal Chemistry Letters
- publisher
- Elsevier
- external identifiers
-
- pmid:22055239
- scopus:84855878223
- pmid:22055239
- ISSN
- 0960-894X
- DOI
- 10.1016/j.bioorg.2011.10.001
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Organic chemistry (S/LTH) (011001240)
- id
- 0ab603cf-87e3-44a3-9662-042b59164252 (old id 2221123)
- date added to LUP
- 2016-04-01 10:55:07
- date last changed
- 2022-01-26 03:40:26
@article{0ab603cf-87e3-44a3-9662-042b59164252,
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.}},
author = {{Nilsson, Jakob and Ostergaard Nielsen, Elsebet and Liljefors, Tommy and Nielsen, Mogens and Sterner, Olov}},
issn = {{0960-894X}},
language = {{eng}},
month = {{10}},
publisher = {{Elsevier}},
series = {{Bioorganic & Medicinal Chemistry Letters}},
title = {{3-Alkyl- and 3-amido-isothiazoloquinolin-4-ones as ligands for the benzodiazepine site of GABA(A) receptors.}},
url = {{http://dx.doi.org/10.1016/j.bioorg.2011.10.001}},
doi = {{10.1016/j.bioorg.2011.10.001}},
year = {{2011}},
}