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
| Autor: | Livio Luongo, Roger G. Pertwee, Ruin Moaddel, Daniele Bolognini, Maria Grazia Cascio, Stefania Dragoni, Luca Bellucci, Alessia Ligresti, Maria De Chiaro, Massimo Valoti, Sabatino Maione, Federico Corelli, Stefania Nocerino, Claudia Mugnaini, Andrea Tafi, Avraham Rosenberg, Serena Pasquini, Vincenzo Di Marzo, Francesca Guida, Valentina Pedani |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Stereochemistry Metabolite medicine.medical_treatment Carboxylic Acids CHO Cells Ligands Biochemistry Article Receptor Cannabinoid CB2 chemistry.chemical_compound Mice Structure-Activity Relationship Cricetulus Amide Cell Line Tumor Cricetinae Drug Discovery medicine Side chain Structure–activity relationship Inverse agonist Peptide bond Animals Humans Computer Simulation General Pharmacology Toxicology and Pharmaceutics Chromatography High Pressure Liquid Pharmacology 4-Quinolones Molecular Structure Chemistry Organic Chemistry Lipids Protein Structure Tertiary Solubility Molecular Medicine Cannabinoid Linker |
| Zdroj: | ChemMedChem. 7(5) |
| ISSN: | 1860-7187 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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