Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 2. Synthesis and Structure-Activity Relationship of Potent and Selective Cannabinoid-2 Receptor Agonists Endowed with Analgesic Activity in Vivo.

A set of quinolone-3-carboxamides 11 bearing at position 5, 6, 7, or 8 diverse substituents, such as halides, alkyl, aryl, alkoxy, and aryloxy groups, differing for their steric/electronic properties, was prepared. The new compounds were tested in vitro for CB1 and CB2 receptor affinity in comparison with the reference compounds rimonabant and SR144528. The tested compounds exhibited CB2 affinity in the range 55.9 nM to 0.8 nM, and CB1 affinity in the range >10,000 nM to 5.3 nM, with selectivity indeces [Ki(CB1)/Ki(CB2)] varying from >2,666.6 to 1.23. Based on the structure-selectivity relationship developed, the presence of a substituent at C6/C8 or C7 well accounts for the high or low CB2 selectivity, respectively. Compound 11c, characterized by high CB2 affinity and selectivity showed analgesic activity in the formalin test of acute peripheral and inflammatory pain in mice, as a result of selective CB2 agonistic activity.