American Chemical Society
jm050467q_si_001.pdf (172.11 kB)

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

Download (172.11 kB)
journal contribution
posted on 2006-01-12, 00:00 authored by Eric Stern, Giulio G. Muccioli, Régis Millet, Jean-François Goossens, Amaury Farce, Philippe Chavatte, Jacques H. Poupaert, Didier M. Lambert, Patrick Depreux, Jean-Pierre Hénichart
Recent data indicated that the CB2 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 CB1 and CB2 cannabinoid receptors. The results indicate that these 3-carboxamido-quinolones derivatives exhibited a CB2 receptor selectivity, particularly derivatives 2830, and 32R. Moreover, in the [35S]-GTPγS binding assay, all the compounds behaved as CB2 receptor agonists. Molecular modeling studies showed that compound 30 interacts with the CB2 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 CB2 cannabinoid receptors agonists.