Gambacorta, NicolaGasperi, ValeriaGuzzo, TatianaSaverio Di Levada, FrancescoCiriaco, FulvioSánchez García, María CristinaTullio, ValentinaRozzi, DiegoMarinelli, LucianaTopai, AlessandraNicolotti, OrazioMaccarrone, Mauro2024-03-202024-03-202023-07-140223-523410.1016/j.ejmech.2023.115647https://hdl.handle.net/20.500.14352/102415The discovery of selective agonists of cannabinoid receptor 2 (CB2) is strongly pursued to successfully tuning endocannabinoid signaling for therapeutic purposes. However, the design of selective CB2 agonists is still challenging because of the high homology with the cannabinoid receptor 1 (CB1) and for the yet unclear molecular basis of the agonist/antagonist switch. Here, the 1,3-benzoxazine scaffold is presented as a versatile chemotype for the design of CB2 agonists from which 25 derivatives were synthesized. Among these, compound 7b5 (CB2 EC50 = 110 nM, CB1 EC50 > 10 μM) demonstrated to impair proliferation of triple negative breast cancer BT549 cells and to attenuate the release of pro-inflammatory cytokines in a CB2-dependent manner. Furthermore, 7b5 abrogated the activation of extracellular signal-regulated kinase (ERK) 1/2, a key pro-inflammatory and oncogenic enzyme. Finally, molecular dynamics studies suggested a new rationale for the in vitro measured selectivity and for the observed agonist behavior.engjournal articlehttps://www.sciencedirect.com/science/article/pii/S022352342300613Xrestricted access577.1615.91,3-Benzoxazin-4-oneInflammationCancerCB2Neurodegenerative disordersNeuropathic painBioquímica (Biología)Oncología2403 Bioquímica3201.01 Oncología