1. 1,2-Dihydro-2-oxopyridine-3-carboxamides: The C-5 substituent is responsible for functionality switch at CB2 cannabinoid receptor.
- Author
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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, and Manera, Clementina
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CARBOXAMIDES , *CANNABINOID receptors , *INFLAMMATION treatment , *NEUROPATHY , *PAIN management , *TREATMENT of neurodegeneration - Abstract
Abstract: 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 (K i = 1.0 nM), accompanied by interesting K i(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. [Copyright &y& Elsevier]
- Published
- 2014
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