Abstract
Neurological and neurodegenerative diseases are debilitating conditions, and frequently lack an effective treatment. Monoacylglycerol lipase (MAGL) is a key enzyme involved in the metabolism of 2-AG (2-arachidonoylglycerol), a neuroprotective endocannabinoid intimately linked to the generation of pro- and anti-inflammatory molecules. Consequently, synthesizing selective MAGL inhibitors has become a focus point in drug design and development. The purpose of this review was to summarize the diverse synthetic scaffolds of MAGL inhibitors concerning their potency, mechanisms of action and potential therapeutic applications, focusing on the results of studies published in the past five years. The main irreversible inhibitors identified were derivatives of hexafluoroisopropyl alcohol carbamates, glycol carbamates, azetidone triazole ureas and benzisothiazolinone, whereas the most promising reversible inhibitors were derivatives of salicylketoxime, piperidine, pyrrolidone and azetidinyl amides. We reviewed the results of in-depth chemical, mechanistic and computational studies on MAGL inhibitors, in addition to the results of in vitro findings concerning selectivity and potency of inhibitors, using the half maximal inhibitory concentration (IC50) as an indicator of their effect on MAGL. Further, for highlighting the potential usefulness of highly selective and effective inhibitors, we examined the preclinical in vivo reports regarding the promising therapeutic applications of MAGL pharmacological inhibition.
Highlights
Accepted: 15 September 2021Monoacylglycerol lipase (MAGL; EC 3.1.1.23) is a membrane-bound α/β serine hydrolase, which selectively metabolizes 2-monoacylglycerols [1]
The usage of computer-aided drug design (CADD) tools has been widely preferred in the rational drug discovery of MAGL inhibitors, with several research groups employing CADD approaches on several chemical scaffolds to discover and identify novel
From the analysis of available data concerning MAGL reversible inhibition, the key pharmacophoric elements that appear to be important for inhibitory activity are: (a) a carbonyl group able to interact in the oxyanion hole of the enzyme, (b) an aromatic portion comprising a heterocyclic nucleus involved in van der Waals interactions in a closed hydrophobic region of the binding site, and (c) a second aromatic portion, which interacts in the opening [29]
Summary
Monoacylglycerol lipase (MAGL; EC 3.1.1.23) is a membrane-bound α/β serine hydrolase, which selectively metabolizes 2-monoacylglycerols [1]. 2-AG is one of the most abundant endocannabinoids and plays an essential role in the regulation of many physiological processes It modulates neuroplasticity and neuroprotection by mediating retrograde suppression of inhibitory or excitatory currents in GABAergic and glutamatergic synapses [3] by activating CB1R receptors [4]. 2-AG appears to regulate metabolism, cell proliferation, pain sensation, and reproductive and cardiovascular functions [6,7], by activating CB2R receptors and other targets (peroxisome proliferator-activated receptors, transient receptor potential vanilloid-1) [7] (Figure 1). 3; GABA-A receptorsγ-Aminobutyric acid type A receptors; PPAR-γ proliferator-activated γ receptors; GPR55—G protein-coupled receptor. MAGL appears to be the main enzyme involved in AA synthesis in the brain, liver, and lung [10,11]. Some recent identified irreversible inhibitors present a good pharmacokinetic cokinetic and effective are highly reducing inflammation in vivo [15,16]. 2015 and 2021—a period of intense research in this emerging field
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