1,2-Dihydro-2-oxopyridine-3-carboxamides: The C-5 substituent is responsible for functionality switch at CB2 cannabinoid receptor

The relevance of CB2R-mediated therapeutic effects is well-known for the treatment of inflammatory and neuropathic pain and neurodegenerative disorders. In our search for new cannabinoid receptor modulators, we report the optimization of a series of 1,2-dihydro-2-oxopyridine-3-carboxamide derivative...

Full description

Saved in:
Bibliographic Details
Published in:European journal of medicinal chemistry 2014-03, Vol.74, p.524-532
Main Authors: Lucchesi, Valentina, Parkkari, Teija, Savinainen, Juha R., Malfitano, Anna Maria, Allarà, Marco, Bertini, Simone, Castelli, Francesca, Del Carlo, Sara, Laezza, Chiara, Ligresti, Alessia, Saccomanni, Giuseppe, Bifulco, Maurizio, Di Marzo, Vincenzo, Macchia, Marco, Manera, Clementina
Format: Article
Language:English
Subjects:
Cannabinoid
CB1 receptor
CB2 receptor
CB2 receptor inverse agonist
CB2 receptor neutral antagonist
HEK293 Cells
Humans
Magnetic Resonance Spectroscopy
Mass Spectrometry
Protein Binding
Pyridines - chemistry
Pyridines - pharmacology
Receptor, Cannabinoid, CB2 - drug effects
Receptor, Cannabinoid, CB2 - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The relevance of CB2R-mediated therapeutic effects is well-known for the treatment of inflammatory and neuropathic pain and neurodegenerative disorders. In our search for new cannabinoid receptor modulators, we report the optimization of a series of 1,2-dihydro-2-oxopyridine-3-carboxamide derivatives as CB2R ligands. In particular, N-cycloheptyl-5-(4-methoxyphenyl)-1-(4-fluorobenzyl)-pyridin-2(1H)-on-3-carboxamide (17) showed high CB2R affinity (Ki = 1.0 nM), accompanied by interesting Ki(CB1R)/Ki(CB2R) selectivity ratio (SI = 43.4). Compound 17 was also identified as a potent CB2R neutral antagonist/weak partial inverse agonist. Finally we found that the functionality activity of the series of 1,2-dihydro-2-oxopyridine is controlled by the presence of a substituent in position 5 of the heterocyclic nucleus. In fact when the hydrogen atom in position 5 of the unsubstituted compound 1 was replaced with a phenyl group (compound 18) the CB2R activity was shifted from agonism to inverse agonism whereas the introduction in the same position of p-methoxyphenyl group lead to compound 17 which showed a behavior as CB2R neutral antagonist/weak partial inverse agonist. [Display omitted] •We report the study of 1,2-dihydro-2-oxopyridine-3-carboxamides as new CB2R ligands.•The 5-substituted derivatives possess CB2R affinity in the low nM range.•We identify the key position of the central nucleus for functionality switch.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2013.10.070