Development of N-(1-Adamantyl)benzamides as Novel Anti-Inflammatory Multitarget Agents Acting as Dual Modulators of the Cannabinoid CB2 Receptor and Fatty Acid Amide Hydrolase

Cannabinoid type 2 receptor (CB2R), belonging to the endocannabinoid system, is overexpressed in pathologies characterized by inflammation, and its activation counteracts inflammatory states. Fatty acid amide hydrolase (FAAH) is an enzyme responsible for the degradation of the main endocannabinoid a...

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Detalles Bibliográficos
Autores: Intranuovo, F., Brunetti, L., Delre, P., Mangiatordi, G.F., Stefanachi, A., Laghezza, A., Niso, M., Leonetti, F., Loiodice, F., Ligresti, A., Kostrzewa, M., Brea Floriani, José Manuel, Loza García, María Isabel, Sotelo, E., Saviano, M., Colabufo, N.A., Riganti, C., Abate, C., Contino, M.
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Servizo Galego de Saúde (SERGAS)
Repositorio:RUNA. Repositorio da Consellería de Sanidade e Sergas
OAI Identifier:oai:runa.sergas.gal:20.500.11940/21397
Acceso en línea:https://portalcientifico.sergas.gal//documentos/63b996df4386723d2da378bb
http://hdl.handle.net/20.500.11940/21397
Access Level:acceso abierto
Palabra clave:Cannabinoids
Endocannabinoids
Receptor, Cannabinoid, CB2
Molecular Docking Simulation
Benzamides
Anti-Inflammatory Agents
Amidohydrolases
Cannabinoid Receptor Agonists
Receptor, Cannabinoid, CB1
AS Santiago
IDIS
Descripción
Sumario:Cannabinoid type 2 receptor (CB2R), belonging to the endocannabinoid system, is overexpressed in pathologies characterized by inflammation, and its activation counteracts inflammatory states. Fatty acid amide hydrolase (FAAH) is an enzyme responsible for the degradation of the main endocannabinoid anandamide; thus, the simultaneous CB2R activation and FAAH inhibition may be a synergistic anti-inflammatory strategy. Encouraged by principal component analysis (PCA) data identifying a wide chemical space shared by CB2R and FAAH ligands, we designed a small library of adamantyl-benzamides, as potential dual agents, CB2R agonists, and FAAH inhibitors. The new compounds were tested for their CB2R affinity/selectivity and CB2R and FAAH activity. Derivatives 13, 26, and 27, displaying the best pharmacodynamic profile as CB2R full agonists and FAAH inhibitors, decreased pro-inflammatory and increased anti-inflammatory cytokines production. Molecular docking simulations complemented the experimental findings by providing a molecular rationale behind the observed activities. These multitarget ligands constitute promising anti-inflammatory agents.

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