Rational Design, Synthesis and Biological Evaluation of New Cannabinoid CB2 Receptor Ligands

This Phd thesis is focused on the research for CB2 selective ligands. Several compounds, based on the previously reported 1,8-naphthyridin-2(1H)-one derivatives (Manera et al., 2009), were synthesized, screened for binding and activity at human cannabinoid receptors. Generally, these compounds exhibited a remarkable CB2 affinity, with a Ki value in the nanomolar range, and high selectivity with respect to CB1 receptor. Some agonists and antagonists/inverse agonists were identified within this series. Interestingly data obtained demonstrated to act as agonists or inverse agonists/antagonists in functional activity assays, depending on the presence of the substituents at position C-6 of the naphthyridine scaffold. Docking studies confirmed that the introduction of substituents in this position determined a functionality switch from agonist to antagonist. Moreover one of these compounds has been chose for development of new candidate for PET imaging of CB2 receptor. Finally, using our previously described series of 1,8-naphthyridin-2(1H)- on-3-carboxamides as a lead class, several nitrogen heterocyclic derivatives, characterized by different central cores C-F, were synthesized and tested for their affinity toward the human CB1 and CB2 cannabinoid receptors. The obtained results suggest that the new series of quinolin-2(1H)-on-3-carboxamides, 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides and 1,2-dihydro-2-oxopyridine-3-carboxamides represent novel scaffolds very suitable for the development of promising CB2 ligands. Furthermore some of these compounds exerted anti-proliferative effects on LNCaP cell line.