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.

A set of quinolone-3-carboxamides 2 bearing diverse substituents at position 1, 3, and 6 of the bicyclic nucleus was prepared. Except for six compounds exhibiting K-i > 100 nM, all the quinolone-3-carboxamides 2 proved to be high affinity CB2 ligands, with K-i values ranging from 73.2 to 0.7 nM and selectivity [SI = K-i(CB1)/K-i(CB2)] varying from > 14285 to 1.9, with only 2ah exhibiting a reverse selectivity (SI < 1). In the formalin test of peripheral acute and inflammatory pain in mice, 2ae showed analgesic activity that was antagonized by a selective CB2 antagonist. By contrast, 2e was inactive per se and antagonized the effect of a selective CB2 agonist. Finally, 2g and 2p exhibited CB2 inverse agonist-like behavior in this in vivo test. However, two different functional assays carried out in vitro on 2e and 2g indicated for both compounds an overall inverse agonist activity at CB2 receptors.