Affinity of 3-acyl substituted 4-quinolones at the benzodiazepine site of GABAA receptors

被引：19

作者：

Lager, Erik ^{[1
]}

Nilsson, Jakob ^{[1
]}

Nielsen, Elsebet Ostergaard ^{[2
]}

Nielsen, Mogens ^{[3
]}

Liljefors, Tommy ^{[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 & MEDICINAL CHEMISTRY | 2008年 / 16卷 / 14期

关键词：

3-acyl-1,4-dihydro-4-oxoquinolines; benzodiazepine binding site; GABA(A) receptor; GABA(A) receptor subtypes; pharmacophore model;

D O I：

10.1016/j.bmc.2008.05.049

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：

The finding that alkyl 1,4-dihydro-4-oxoquinoline-3-carboxylate and N-alkyl-1,4-dihydro-4-oxoquinoline3-carboxamide derivatives may be high-affinity ligands at the benzodiazepine binding site of the GABA(A) receptor, prompted a study of 3-acyl-1,4-dihydro-4-oxoquinoline (3-acyl-4-quinolones). In general, the affinity of the 3-acyl derivatives was found to be comparable with the 3-carboxylate and the 3-carboxamide derivatives, and certain substituents ( e. g., benzyl) in position 6 were again shown to be important. As it is believed that the benzodiazepine binding site is situated between an alpha-and a gamma-subunit in the GABA(A) receptor, selected compounds were tested on the alpha(1)beta(2)gamma(2s), alpha(2)beta(2)gamma(2s) and alpha(3)beta(2)gamma(2s) GABAA receptor subtypes. The 3-acyl-4-quinolones display various degrees of selectivity for alpha(1)-versus alpha(2)- and alpha(3)- containing receptors, and high-affinity ligands essentially selective for alpha(1) over alpha(3) were developed. (c) 2008 Elsevier Ltd. All rights reserved.

引用

页码：6936 / 6948

页数：13

共 40 条

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