3-Alkyl- and 3-amido-isothiazoloquinolin-4-ones as ligands for the benzodiazepine site of GABAA receptors

被引：6

作者：

Nilsson, Jakob ^{[1
]}

Nielsen, Elsebet Ostergaard ^{[2
]}

Liljefors, Tommy ^{[3
]}

Nielsen, Mogens ^{[3
]}

Sterner, Olov ^{[1
]}

机构：

[1] Lund Univ, Div Organ Chem, SE-22100 Lund, Sweden

[2] NeuroSearch AS, DK-2750 Ballerup, Denmark

[3] Univ Copenhagen, Fac Pharmaceut Sci, DK-2100 Copenhagen, Denmark

来源：

BIOORGANIC CHEMISTRY | 2012年 / 40卷

关键词：

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; BINDING; PHARMACOLOGY; DERIVATIVES; AFFINITY;

D O I：

10.1016/j.bioorg.2011.10.001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. (C) 2011 Elsevier Inc. All rights reserved.

引用

页码：125 / 130

页数：6

共 10 条

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