Studies of molecular pharmacophore/receptor models for GABAA/BzR subtypes: binding affinities of symmetrically substituted pyrazolo[4,3-c]quinolin-3-ones at recombinant alpha x beta 3 gamma 2 subtypes and quantitative structure-activity relationship studies via a comparative molecular field analysis.
A series of symmetrically substituted pyrazoloquinolinones was synthesized to probe the BzR binding site of different GABAA/Bz receptor subtypes. The affinities of the ligands for different BzR subtypes have been determined by radioligand binding assays on 5 distinct recombinant GABAA receptor isoforms [alpha x beta 3 gamma 2 (x = 1,2,3,5, or 6)]. Most of the ligands synthesized exhibited potent biological activity in vitro. Among them, 3 ligands exhibited enhanced affinity for the alpha 2 beta 3 gamma 2 subtype in comparison to the other subtypes, six ligands demonstrated higher affinity for the alpha 3 beta 3 gamma 2 subtype, while 2 ligands showed some enhanced affinity for the alpha 5 beta 3 gamma 2 subtype. The remainder of the ligands exhibited relatively higher affinities at the alpha 1 containing subtype. To map out the steric and electronic differences between the benzodiazepine binding subtypes, a QSAR analysis by the method of Comparative Molecular Field Analysis (CoMFA) of each receptor subtypes was carried out.
He
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X
Department of Chemistry, University of Wisconsin-Milwaukee 53201-0413, USA.
Huang
Q
Q
Yu
S
S
Ma
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C
McKernan
R
R
Cook
J M
JM
D001665:Binding Sites / Q000502:physiology; D003198:Computer Simulation; D006868:Hydrolysis; D066298:In Vitro Techniques; D008024:Ligands; D020033:Protein Isoforms; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry*; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000145:classification; D011994:Recombinant Proteins; D013329:Structure-Activity Relationship
D008024:Ligands; D020033:Protein Isoforms; D011720:Pyrazoles; D011963:Receptors, GABA-A; D011994:Recombinant Proteins