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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 ; Allarà, Marco ; Bertini, Simone ; Castelli, Francesca ; Del Carlo, Sara ; Laezza, Chiara ; Ligresti, Alessia ; Saccomanni, Giuseppe ; Bifulco, Maurizio ; Di Marzo, Vincenzo ; Macchia, Marco ; Manera, Clementina

European journal of medicinal chemistry, 2014-03, Vol.74, p.524-532 [Periódico revisado por pares]

France: Elsevier Masson SAS

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Título:
1,2-Dihydro-2-oxopyridine-3-carboxamides: The C-5 substituent is responsible for functionality switch at CB2 cannabinoid receptor
Autor: 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
Assuntos: 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
É parte de: European journal of medicinal chemistry, 2014-03, Vol.74, p.524-532
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Descrição: 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.
Editor: France: Elsevier Masson SAS
Idioma: Inglês

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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 ; Allarà, Marco ; Bertini, Simone ; Castelli, Francesca ; Del Carlo, Sara ; Laezza, Chiara ; Ligresti, Alessia ; Saccomanni, Giuseppe ; Bifulco, Maurizio ; Di Marzo, Vincenzo ; Macchia, Marco ; Manera, Clementina

France: Elsevier Masson SAS

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