title: 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.
authors.affiliation: Institut de Chimie Pharmaceutique Albert Lespagnol, Université de Lille 2, EA 2692, 3 rue du Pr. Laguesse, B.P. 83, F-59006 Lille, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Stern
authors.forename: Giulio G
authors.initials: GG
authors.lastname: Muccioli
authors.forename: Régis
authors.initials: R
authors.lastname: Millet
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Goossens
authors.forename: Amaury
authors.initials: A
authors.lastname: Farce
authors.forename: Philippe
authors.initials: P
authors.lastname: Chavatte
authors.forename: Jacques H
authors.initials: JH
authors.lastname: Poupaert
authors.forename: Didier M
authors.initials: DM
authors.lastname: Lambert
authors.forename: Patrick
authors.initials: P
authors.lastname: Depreux
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hénichart
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D015363:Quinolones; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2