1579273-53-2Relevant academic research and scientific papers
1,2-Dihydro-2-oxopyridine-3-carboxamides: The C-5 substituent is responsible for functionality switch at CB2 cannabinoid receptor
Lucchesi, Valentina,Parkkari, Teija,Savinainen, Juha R.,Malfitano, Anna Maria,Allara, Marco,Bertini, Simone,Castelli, Francesca,Del Carlo, Sara,Laezza, Chiara,Ligresti, Alessia,Saccomanni, Giuseppe,Bifulco, Maurizio,Di Marzo, Vincenzo,Macchia, Marco,Manera, Clementina
, p. 524 - 532 (2014/03/21)
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)/K i(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.
