Serena Pasquini, Alessia Ligresti, Claudia Mugnaini, Teresa Semeraro, Lavinia Cicione, Maria De Rosa, Francesca Guida, Livio Luongo, Maria De Chiaro, Maria Grazia Cascio, Daniele Bolognini, Pietro Marini, Roger Pertwee, Sabatino Maione, Vincenzo Di Marzo, and Federico Corelli
A set of quinolone-3-carboxamides 2bearing 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 2proved to be high affinity CB2 ligands, with Kivalues ranging from 73.2 to 0.7 nM and selectivity [SI = Ki(CB1)/Ki(CB2)] varying from >14285 to 1.9, with only 2ahexhibiting a reverse selectivity (SI < 1). In the formalin test of peripheral acute and inflammatory pain in mice, 2aeshowed analgesic activity that was antagonized by a selective CB2 antagonist. By contrast, 2ewas inactive per se and antagonized the effect of a selective CB2 agonist. Finally, 2gand 2pexhibited CB2 inverse agonist-like behavior in this in vivo test. However, two different functional assays carried out in vitro on 2eand 2gindicated for both compounds an overall inverse agonist activity at CB2 receptors. [ABSTRACT FROM AUTHOR]