Synthesis and pharmacological evaluation of pyrazolo[4,3-c]quinolinones as high affinity GABA A -R ligands and potential anxiolytics

• Published in: Bioorganic & medicinal chemistry Vol. 26; no. 14; p. 3967
• Main Authors: López Rivilli, Marisa J, Turina, Anahí V, Bignante, Elena A, Molina, Victor H, Perillo, María A, Briñon, Margarita C, Moyano, Elizabeth L
• Format: Journal Article
• Language: English
• Published: England 07.08.2018
• Subjects: Animals; Anti-Anxiety Agents - chemical synthesis; Anti-Anxiety Agents - chemistry; Anti-Anxiety Agents - pharmacology; Anxiety - drug therapy; Behavior, Animal - drug effects; Dose-Response Relationship, Drug; Ligands; Male; Maze Learning - drug effects; Molecular Structure; Quinolones - chemical synthesis; Quinolones - chemistry; Quinolones - pharmacology; Rats; Rats, Wistar; Receptors, GABA-A - metabolism; Structure-Activity Relationship; Benzodiazepine binding; GABA(A) receptor; Elevated plus maze; Pyrazoloquinolinones
• ISSN: 1464-3391

The synthesis, in vitro ligand binding study and in vivo Elevated Plus Maze test (EPM) of a series of pyrazolo[4,3-c]quinolin-3-ones (PQs) are reported. Multistep synthesis of PQs started from anilines and diethyl 2-(ethoxymethylene)malonate to give the quinolin-4-one nucleus, via the Gould-Jacobs reaction. These quinolinones were transformed to 4-chloroquinolines, which react with aryl-hydrazines affording the final compounds. PQs exhibited different potency in displacing specific [ H]Flunitrazepam binding from the benzodiazepine binding site at the γ-aminobutyric acid receptor (GABA -R) depending on the substitution of the pyrazoloquinolone nucleus. PCA helped determine how different substituents contributed to the differential behavior of the PQs studied. Compounds with high affinity for the GABA -R were tested regarding their anxiolytic properties in Wistar adult male rats using the Elevated Plus Maze (EPM). Thus, PQs with a p-methoxy phenyl group at N-1 (7b-ii and 7c-ii) displayed a remarkable anxiolytic activity at low doses (0.5-1.0 mg/kg). Meanwhile, PQs featuring an unsubstituted phenyl (7b-i) or p-fluoro phenyl group (7b-iii) at the N-1 showed anxiogenic effects in the EPM test.