title: Investigations on the 4-quinolone-3-carboxylic acid motif part 5: modulation of the physicochemical profile of a set of potent and selective cannabinoid-2 receptor ligands through a bioisosteric approach.
abstract: Three heterocyclic systems were selected as potential bioisosteres of the amide linker for a series of 1,6-disubstituted-4-quinolone-3-carboxamides, which are potent and selective CB2 ligands that exhibit poor water solubility, with the aim of improving their physicochemical profile and also of clarifying properties of importance for amide bond mimicry. Among the newly synthesized compounds, a 1,2,3-triazole derivative (1-(adamantan-1-yl)-4-[6-(furan-2-yl)-1,4-dihydro-4-oxo-1-pentylquinolin-3-yl]-1H-1,2,3-triazole) emerged as the most promising in terms of both physicochemical and pharmacodynamic properties. When assayed in vitro, this derivative exhibited inverse agonist activity, whereas, in the formalin test in mice, it produced analgesic effects antagonized by a well-established inverse agonist. Metabolic studies allowed the identification of a side chain hydroxylated derivative as its only metabolite, which, in its racemic form, still showed appreciable CB2 selectivity, but was 150-fold less potent than the parent compound.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Siena, Italy. claudia.mugnaini@unisi.it
authors.forename: Claudia
authors.initials: C
authors.lastname: Mugnaini
authors.forename: Stefania
authors.initials: S
authors.lastname: Nocerino
authors.forename: Valentina
authors.initials: V
authors.lastname: Pedani
authors.forename: Serena
authors.initials: S
authors.lastname: Pasquini
authors.forename: Andrea
authors.initials: A
authors.lastname: Tafi
authors.forename: Maria
authors.initials: M
authors.lastname: De Chiaro
authors.forename: Luca
authors.initials: L
authors.lastname: Bellucci
authors.forename: Massimo
authors.initials: M
authors.lastname: Valoti
authors.forename: Francesca
authors.initials: F
authors.lastname: Guida
authors.forename: Livio
authors.initials: L
authors.lastname: Luongo
authors.forename: Stefania
authors.initials: S
authors.lastname: Dragoni
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.forename: Avraham
authors.initials: A
authors.lastname: Rosenberg
authors.forename: Daniele
authors.initials: D
authors.lastname: Bolognini
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cascio
authors.forename: Roger G
authors.initials: RG
authors.lastname: Pertwee
authors.forename: Ruin
authors.initials: R
authors.lastname: Moaddel
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Federico
authors.initials: F
authors.lastname: Corelli
mesh_terms: D042462:4-Quinolones / Q000737:chemistry*; D000818:Animals; D016466:CHO Cells; D002264:Carboxylic Acids / Q000737:chemistry*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D042462:4-Quinolones; D002264:Carboxylic Acids; D008024:Ligands; D008055:Lipids; D043885:Receptor, Cannabinoid, CB2