Affinity of 3-acyl substituted 4-quinolones at the benzodiazepine site of GABAA receptors
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Affinity of 3-acyl substituted 4-quinolones at the benzodiazepine site of GABAA receptors. / Lager, Erik; Nilsson, Jakob; Nielsen, Elsebet Østergaard; Nielsen, Mogens Peter Cherly; Liljefors, Tommy; Sterner, Olov.
I: Bioorganic & Medicinal Chemistry, Bind 16, Nr. 14, 2008, s. 6936-6948.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Affinity of 3-acyl substituted 4-quinolones at the benzodiazepine site of GABAA receptors
AU - Lager, Erik
AU - Nilsson, Jakob
AU - Nielsen, Elsebet Østergaard
AU - Nielsen, Mogens Peter Cherly
AU - Liljefors, Tommy
AU - Sterner, Olov
N1 - Keywords: 4-Quinolones; Animals; Benzodiazepines; Binding Sites; Ligands; Protein Binding; Protein Subunits; Receptors, GABA-A; Structure-Activity Relationship
PY - 2008
Y1 - 2008
N2 - The finding that alkyl 1,4-dihydro-4-oxoquinoline-3-carboxylate and N-alkyl-1,4-dihydro-4-oxoquinoline-3-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) GABA(A) 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.
AB - The finding that alkyl 1,4-dihydro-4-oxoquinoline-3-carboxylate and N-alkyl-1,4-dihydro-4-oxoquinoline-3-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) GABA(A) 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.
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.1016/j.bmc.2008.05.049
DO - 10.1016/j.bmc.2008.05.049
M3 - Journal article
C2 - 18541432
VL - 16
SP - 6936
EP - 6948
JO - Bioorganic & Medicinal Chemistry
JF - Bioorganic & Medicinal Chemistry
SN - 0968-0896
IS - 14
ER -
ID: 10159584