4-Oxo-1,4-dihydropyridines as Selective CB 2 Cannabinoid Receptor Ligands: Structural Insights into the Design of a Novel Inverse Agonist Series - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2010

4-Oxo-1,4-dihydropyridines as Selective CB 2 Cannabinoid Receptor Ligands: Structural Insights into the Design of a Novel Inverse Agonist Series

Résumé

Growing evidence shows that CB2 receptor is an attractive therapeutic target. Starting from a series of 4-oxo-1,4-dihydroquinoline-3-carboxamide as selective CB2 agonists, we describe here the medicinal chemistry approach leading to the development of CB2 receptor inverse agonists with a 4-oxo-1,4-dihydropyridine scaffold. The compounds reported here show high affinity and potency at the CB2 receptor while showing only modest affinity for the centrally expressed CB1 cannabinoid receptor. Further, we found that the functionality of this series is controlled by its C-6 substituent because agonists bear a methyl or a tert-butyl group and inverse agonists, a phenyl or 4-chlorophenyl group, respectively. Finally, in silico studies suggest that the C-6 substituent could modulate the conformation of W6.48 known to be critical in GPCR activation.
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Dates et versions

hal-01936361 , version 1 (27-11-2018)

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Jamal El Bakali, Giulio G. Muccioli, Nicolas Renault, Delphine Pradal, Mathilde Body-Malapel, et al.. 4-Oxo-1,4-dihydropyridines as Selective CB 2 Cannabinoid Receptor Ligands: Structural Insights into the Design of a Novel Inverse Agonist Series. Journal of Medicinal Chemistry, 2010, 53 (22), pp.7918 - 7931. ⟨10.1021/jm100286k⟩. ⟨hal-01936361⟩
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