ETD

• MAGL
• MAGL reversible inhibitors

Monoacylglycerol lipase (MAGL) is a cytosolic serine hydrolase that plays a major role in the degradation of 2-arachidonoylglycerol, an endocannabinoid neurotransmitter implicated in many physiological and pathological processes, such as pain, inflammation, neuroprotection and cancer. MAGL is upregulated in aggressive cancer cells and primary tumors, where it has a unique role of providing a lipolytic source of free fatty acids for the synthesis of oncogenic signalling lipids, which promote cancer aggressiveness. Recent studies have suggested the possible use of MAGL inhibitors as anti-inflammatory, anti-nociceptive and anti-cancer agents. However, the administration of irreversible MAGL inhibitors may determine an unwanted chronic MAGL inactivation, which causes physical dependence, impairs endocannabinoid-dependent synaptic plasticity and desensitises brain CB1 receptors. Therefore, the aim of my thesis is the synthesis of reversible MAGL inhibitors.