Novel 4-Oxo-1,4-dihydroquinoline-3-carboxamide Derivatives as New CB2 Cannabinoid Receptors Agonists: Synthesis, Pharmacological Properties and Molecular Modeling

Abstract

Recent data indicated that the CB(2) cannabinoid receptor constitutes an attractive drug target due to its potential functional role in several physiological and pathological processes. A set of 4-oxo-1,4-dihydroquinoline-3-carboxamide derivatives, characterized by the presence of some important structural requirements exhibited by other classes of cannabinoid ligands, such as an aliphatic or aromatic carboxamide group in position 3, and an alkyl or benzyl group in position 1, was synthesized and assayed to measure their respective affinity for both human CB(1) and CB(2) cannabinoid receptors. The results indicate that these 3-carboxamido-quinolones derivatives exhibited a CB(2) receptor selectivity, particularly derivatives 28-30, and 32R. Moreover, in the [(35)S]-GTPgammaS binding assay, all the compounds behaved as CB(2) receptor agonists. Molecular modeling studies showed that compound 30 interacts with the CB(2) receptor through a combination of hydrogen bond and aromatic/hydrophobic interactions. In conclusion, 4-oxo-1,4-dihydroquinoline-3-carboxamide derivatives constitute a new class of potent and selective CB(2) cannabinoid receptors agonists.