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
- PASQUINI, SERENA
- MUGNAINI, CLAUDIA
- SEMERARO, TERESA
- DE ROSA, MARIA
- CORELLI, FEDERICO
- LIGRESTI A
- CICIONE L
- GUIDA F
- LUONGO L
- DE CHIARO M
- CASCIO M. G
- BOLOGNINI D
- MARINI P
- PERTWEE R
- MAIONE S
- DI MARZO V
DOIAbstract
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 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 nM and selectivity [SI=Ki(CB1)/Ki(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 agonistlike behavior in this in vivo test. However...
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