The endocannabinoid system includes two pharmacologically distinct receptors (the CB1 and CB2 receptor) and it is implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and organs. Pharmacological studies conducted in vitro and in animal models have highlighted the role of CB2 receptor activation in apoptosis induction and inhibition of tumour cell growth which are related to an increase of ceramide levels. Our research is focused on the design and synthesis of selective CB2 cannabinoid receptor agonists to minimize/avoid the typical marijuana-like psychoactive effects mediated by CB1 receptor. The development of new lead characterized by heterocyclic core have been developed having recourse to molecular modeling and binding assay data. Until now some of the molecules developed show an appreciable selectivity and an high affinity (in the nanomolar range) towards CB2 receptor. The most promising ligands obtained were tested in vitro and in vivo models to evaluate its anticancer activity. Recently for some fluorinated leads, using innovative approaches, we have synthesized [18F]-labelled analogues to evaluate its in vivo biodistribution through PET imaging. These [18F]-labelled compounds represent a starting point for research on new potential imaging biomarkers for pathological conditions characterized by an overexpression of CB2 receptor. Furthermore all these studies have allowed to obtain significant information for the development of new selective CB2 ligands as candidates for cannabinoid-based anticancer therapy and to investigate the involvement and signaling pathway of this receptor in several diseases.

Rational design, synthesis, biological evaluation and labelling of selective cannabinoid CB2 receptor agonists as anticancer agents

SACCOMANNI, GIUSEPPE;BERTINI, SIMONE;DEL CARLO, SARA;TUCCINARDI, TIZIANO;MACCHIA, MARCO;MARTINELLI, ADRIANO;MANERA, CLEMENTINA
2011-01-01

Abstract

The endocannabinoid system includes two pharmacologically distinct receptors (the CB1 and CB2 receptor) and it is implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and organs. Pharmacological studies conducted in vitro and in animal models have highlighted the role of CB2 receptor activation in apoptosis induction and inhibition of tumour cell growth which are related to an increase of ceramide levels. Our research is focused on the design and synthesis of selective CB2 cannabinoid receptor agonists to minimize/avoid the typical marijuana-like psychoactive effects mediated by CB1 receptor. The development of new lead characterized by heterocyclic core have been developed having recourse to molecular modeling and binding assay data. Until now some of the molecules developed show an appreciable selectivity and an high affinity (in the nanomolar range) towards CB2 receptor. The most promising ligands obtained were tested in vitro and in vivo models to evaluate its anticancer activity. Recently for some fluorinated leads, using innovative approaches, we have synthesized [18F]-labelled analogues to evaluate its in vivo biodistribution through PET imaging. These [18F]-labelled compounds represent a starting point for research on new potential imaging biomarkers for pathological conditions characterized by an overexpression of CB2 receptor. Furthermore all these studies have allowed to obtain significant information for the development of new selective CB2 ligands as candidates for cannabinoid-based anticancer therapy and to investigate the involvement and signaling pathway of this receptor in several diseases.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/150638
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