Novel approaches in the field of cancer and neuroinflammation: design, synthesis and biological evaluation of new modulators of the endocannabinoid system and studies on nutraceutical components of olive oil

Cannabinoid receptors (CB1R and CB2R) and endocannabinoid ligands (anandamide and 2-arachidonoylglycerol), together with the enzymes implicated in endocannabinoid biosynthesis, degradation (FAAH, MAGL and ABDHs) and cellular uptake (EMT) constitute the endocannabinoid system (ECS), which is a complex and an ubiquitous system involved in several physiological and pathological processes including cancer, appetite, memory, neuropathic and inflammatory pain, obesity, neuroprotection and neurodegenerative diseases. In a research project aimed at obtaining new CB2R ligands, we developed a series of 6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide derivatives. Interestingly, the substituent in position C5 of the pyridine ring is crucially involved in the switch among the different types of pharmacological modulation (agonism, inverse agonism and antagonism) of CB2R. To further deepen the structure-activity relationships of this class of compounds, the central scaffold was modified following different approaches: a) insertion of all the different halogens at the C5 position of the pyridine ring b) switch of the methyl group from the C4 to the C6 position; c) insertion of bulky substituents at the C4 or C6 position of the pyridine ring. We also tested the 2-oxo-1,2-dihydropyridine-3-carboxamide derivatives on all the main targets of the ECS