title: Investigations on the 4-quinolone-3-carboxylic acid motif. 4. Identification of new potent and selective ligands for the cannabinoid type 2 receptor with diverse substitution patterns and antihyperalgesic effects in mice.
abstract: Experimental evidence suggests that selective CB2 receptor modulators may provide access to antihyperalgesic agents devoid of psychotropic effects. Taking advantage of previous findings on structure-activity/selectivity relationships for a class of 4-quinolone-3-carboxamides, further structural modifications of the heterocyclic scaffold were explored, leading to the discovery of the 8-methoxy derivative 4a endowed with the highest affinity and selectivity ever reported for a CB2 ligand. The compound, evaluated in vivo in the formalin test, behaved as an inverse agonist by reducing at a dose of 6 mg/kg the second phase of the formalin-induced nocifensive response in mice.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Siena, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Pasquini
authors.forename: Maria
authors.initials: M
authors.lastname: De Rosa
authors.forename: Valentina
authors.initials: V
authors.lastname: Pedani
authors.forename: Claudia
authors.initials: C
authors.lastname: Mugnaini
authors.forename: Francesca
authors.initials: F
authors.lastname: Guida
authors.forename: Livio
authors.initials: L
authors.lastname: Luongo
authors.forename: Maria
authors.initials: M
authors.lastname: De Chiaro
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.forename: Stefania
authors.initials: S
authors.lastname: Dragoni
authors.forename: Maria
authors.initials: M
authors.lastname: Frosini
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Federico
authors.initials: F
authors.lastname: Corelli
mesh_terms: D042462:4-Quinolones / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D015363:Quinolones / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects / Q000378:metabolism*
chemical_list: D042462:4-Quinolones; D000700:Analgesics; D008024:Ligands; C561593:N-(adamantan-1-yl)-8-methoxy-4-oxo-1-pentyl-1,4-dihydroquinoline-3-carboxamide; D015363:Quinolones; D043885:Receptor, Cannabinoid, CB2; D000218:Adamantane