Pharmacomodulations around the 4-Oxo-1,4-dihydroquinoline-3-carboxamides, a Class of Potent CB2-Selective Cannabinoid Receptor Ligands:  Consequences in Receptor Affinity and Functionality

• Published in: Journal of medicinal chemistry 2007-11, Vol.50 (22), p.5471-5484
• Main Authors: Stern, Eric, Muccioli, Giulio G, Bosier, Barbara, Hamtiaux, Laurie, Millet, Régis, Poupaert, Jacques H, Hénichart, Jean-Pierre, Depreux, Patrick, Goossens, Jean-François, Lambert, Didier M
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Animals; Binding, Competitive; Biological and medical sciences; CHO Cells; Cricetinae; Cricetulus; Drug Inverse Agonism; Humans; Ligands; Medical sciences; Miscellaneous; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Radioligand Assay; Receptor, Cannabinoid, CB2 - agonists; Receptor, Cannabinoid, CB2 - antagonists & inhibitors; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm070387h

CB2 receptor selective ligands are becoming increasingly attractive drugs due to the potential role of this receptor in several physiopathological processes. Thus, the development of our previously described series of 4-oxo-1,4-dihydroquinoline-3-carboxamides was pursued with the aim to further characterize the structure−affinity and structure−functionality relationships of these derivatives. The influence of the side chain was investigated by synthesizing compounds bearing various carboxamido and keto substituents. On the other hand, the role of the quinoline central scaffold was studied by synthesizing several 6-, 7-, or 8-chloro-4-oxo-1,4-dihydroquinolines, as well as 4-oxo-1,4-dihydronaphthyridine and 4-oxo-1,4-dihydrocinnoline derivatives. The effect of these modifications on the affinity and functionality at the CB2 receptor was studied and allowed for the characterization of new selective CB2 receptor ligands.