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 hetrocyclic 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 behaviour as CB2R neutral antagonist/weak partial inverse agonist.
|Autori:||Valentina, Lucchesi; Teija, Parkkari; Juha R., Savinainen; Anna Maria, Malfitano; Marco, Allarà; Bertini, Simone; Francesca, Castelli; Sara Del, Carlo; Chiara, Laezza; Alessia, Ligresti; Saccomanni, Giuseppe; Maurizio, Bifulco; Vincenzo Di, Marzo; Macchia, Marco; Manera, Clementina|
|Titolo:||1,2-Dihydro-2-oxopyridine-3-carboxamides: the C-5 substituent is responsible for functionality switch at CB2 cannabinoid receptor|
|Anno del prodotto:||2014|
|Digital Object Identifier (DOI):||10.1016/j.ejmech.2013.10.070|
|Appare nelle tipologie:||1.1 Articolo in rivista|