High affinity central benzodiazepine receptor ligands. Part 2: quantitative structure-activity relationships and comparative molecular field analysis of pyrazolo[4,3-c]quinolin-3-ones.
A large series of 2-aryl(heteroaryl)-2,5-dihydropyrazolo[4,3-c]quinolin-3(3H)-ones (PQ, 106 compounds), carrying appropriate substituents at the quinoline and N2-phenyl rings, were designed, prepared and tested as central benzodiazepine receptor ligands. Compounds with an affinity significantly higher than the parent compound CGS-8216 were obtained, the most active ligand showing a pIC50 = 10.35. Hansch and comparative molecular field analyses gave coherent results suggesting the main structural requirements of high receptor binding affinity. The possible formation of a three-centred hydrogen bond (HB) at the HB donor site H2, as a key interaction for high receptor binding affinity, was assessed by the calculation and comparison of the molecular electrostatic potentials of a series of selected ligands.
Dipartimento Farmaco Chimico, Università degli Studi, Bari, Italy.
L
L
Savini
L
L
Chiasserini
C
C
Pellerano
G
G
Biggio
E
E
Maciocco
M
M
Serra
N
N
Cinone
A
A
Carrieri
C
C
Altomare
A
A
Carotti
D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D018755:GABA Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D018756:GABA Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D011485:Protein Binding; D011720:Pyrazoles / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism*; D055672:Static Electricity
D018755:GABA Agonists; D018756:GABA Antagonists; D008024:Ligands; D011720:Pyrazoles; D015363:Quinolones; D011963:Receptors, GABA-A; C033830:2-phenylpyrazolo(4,3-c)quinolin-3(5H)-one