Universidad Nacional de Córdoba, Facultad de Ciencias Químicas Departamento de Química Orgánica and CONICET, Instituto de Investigaciones en Fisico-Química de Córdoba (INFIQC), Córdoba X5000HUA, Argentina.
Universidad Nacional de Córdoba, Facultad de Ciencias Exactas, Físicas y Naturales, Departamento de Química, Biofísica-Química, Cátedra de Química Biológica and CONICET, Instituto de Investigaciones Biológicas y Tecnológicas (IIBYT), Córdoba 5000, Argentina.
Bioorg Med Chem. 2018 Aug 7;26(14):3967-3974. doi: 10.1016/j.bmc.2018.06.021. Epub 2018 Jun 15.
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.
报道了一系列吡唑并[4,3-c]喹啉-3-酮（PQs）的合成、体外配体结合研究和体内高架十字迷宫试验（EPM）。PQs 的多步合成从苯胺和二乙基 2-（乙氧基亚甲基）丙二酸酯开始，通过 Gould-Jacobs 反应得到喹啉-4-酮核。这些喹啉酮转化为 4-氯喹啉，与芳基腙反应得到最终化合物。根据吡唑并喹诺酮核取代基的不同，PQs 在置换特定 [H]氟硝西泮与γ-氨基丁酸受体（GABA-R）结合位点的结合方面表现出不同的效力。PCA 有助于确定不同取代基如何影响所研究的 PQs 的差异行为。用高架十字迷宫（EPM）在 Wistar 成年雄性大鼠中测试对 GABA-R 具有高亲和力的化合物，以研究其抗焦虑特性。因此，在 N-1 位具有对甲氧基苯基取代基的 PQs（7b-ii 和 7c-ii）在低剂量（0.5-1.0mg/kg）时表现出显著的抗焦虑活性。同时，在 N-1 位具有未取代的苯基（7b-i）或对氟苯基取代基（7b-iii）的 PQs 在 EPM 测试中表现出焦虑作用。
