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|Title:||Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 3. Synthesis, Structure-Affinity Relationships, and Pharmacological Characterization of 6-Substituted 4-Quinolone-3-carboxamides as Highly Selective Cannabinoid-2 Receptor Ligands||Authors:||Pasquini, Serena
DE ROSA, Maria
DE CHIARO, M
CASCIO M., G
DI MARZO, V
|Issue Date:||2010||Project:||None||Journal:||JOURNAL OF MEDICINAL CHEMISTRY||Abstract:||
A set of quinolone-3-carboxamides 2 bearing diverse substituents at position 1, 3, and 6 of the bicyclicnucleus was prepared. Except for six compounds exhibiting Ki >100 nM, all the quinolone-3-carboxamides 2 proved to be high affinity CB2 ligands, with Ki values ranging from 73.2 to 0.7 nMand selectivity [SI=Ki(CB1)/Ki(CB2)] varying from >14285 to 1.9, with only 2ah exhibiting a reverseselectivity (SI<1). In the formalin test of peripheral acute and inflammatory pain in mice, 2ae showedanalgesic activity that was antagonized by a selective CB2 antagonist. By contrast, 2e was inactive per seand antagonized the effect of a selective CB2 agonist. Finally, 2g and 2p exhibited CB2 inverse agonistlikebehavior in this in vivo test. However, two different functional assays carried out in vitro on 2e and2g indicated for both compounds an overall inverse agonist activity at CB2 receptors.
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