Abstract
Monoacylglycerol lipase is a serine hydrolase that plays a major role in the degradation of the endocannabinoid neurotransmitter 2-arachidonoylglycerol. A wide number of MAGL inhibitors are reported in literature; however, many of them are characterised by an irreversible mechanism of action and this behavior determines an unwanted chronic MAGL inactivation, which acquires a functional antagonism of the endocannabinoid system. The possible use of reversible MAGL inhibitors has only recently been explored, due to the lack of known compounds possessing efficient reversible inhibitory activities. In this work, we report a new series of terphenyl-2-methyloxazol-5(4H)-one derivatives characterised by a reversible MAGL-inhibition mechanism. Among them, compound 20b showed to be a potent MAGL reversible inhibitor (IC50 = 348 nM) with a good MAGL/FAAH selectivity. Furthermore, this compound showed antiproliferative activities against two different cancer cell lines that overexpress MAGL.
Highlights
Endocannabinoids are lipid transmitters that act as endogenous ligands of the CB1 and CB2 cannabinoid receptors
The endogenous ligands 2-arachidonoylglycerol (2-AG) and N-arachidonoyl ethanolamine (AEA) are considered as the two major endocannabinoids and modulate multiple physiological processes including pain, inflammation, appetite, memory and emotion[1]. Their signaling activity is terminated by enzymatic hydrolysis, which is mainly mediated by serine hydrolase monoacylglicerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), respectively[2]
Over the past 10 years, great efforts have been done for identifying novel MAGL inhibitors[8,9,10,11,12,13]; almost all the reported compounds are characterised by an irreversible MAGL-inhibition mechanism[2]
Summary
Endocannabinoids are lipid transmitters that act as endogenous ligands of the CB1 and CB2 cannabinoid receptors. The endogenous ligands 2-arachidonoylglycerol (2-AG) and N-arachidonoyl ethanolamine (AEA) are considered as the two major endocannabinoids and modulate multiple physiological processes including pain, inflammation, appetite, memory and emotion[1]. Their signaling activity is terminated by enzymatic hydrolysis, which is mainly mediated by serine hydrolase monoacylglicerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), respectively[2]. Chronic MAGL blockade causes impaired endocannabinoid-dependent synaptic plasticity, physical dependence and desensitised brain CB1 receptors[14] Considering all these negative effects associated to the irreversible MAGL inhibition, the need to discover selective and reversible MAGL inhibitors constitutes a challenging opportunity to target MAGL with minimal occurrence of unwanted side effects. In 2016, Tuccinardi et al.[16] reported a novel class of benzoylpiperidine derivatives as potent and selective MAGL reversible inhibitors possessing antiproliferative activity against ovarian cancer cell lines (Figure 1, compound 17b)[17]
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