Affinity of 3-acyl substituted 4-quinolones at the benzodiazepine site of GABA(A) receptors.
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.
Division of Organic Chemistry, Lund University, PO Box 124, SE-221 00 Lund, Sweden.
Erik
E
Lager
Jakob
J
Nilsson
Elsebet
E
Østergaard Nielsen
Mogens
M
Nielsen
Tommy
T
Liljefors
Olov
O
Sterner
D042462:4-Quinolones / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism; D001665:Binding Sites; D008024:Ligands; D011485:Protein Binding; D021122:Protein Subunits; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship
D042462:4-Quinolones; D008024:Ligands; D021122:Protein Subunits; D011963:Receptors, GABA-A; D001569:Benzodiazepines