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Aryl N-[ω-(6-Fluoroindol-1-yl)alkyl]carbamates as Inhibitors of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and Butyrylcholinesterase: Structure-Activity Relationships and Hydrolytic Stability.

ABSTRACT: A series of aryl N-[ω-(6-fluoroindol-1-yl)alkyl]carbamates with alkyl spacers of varying lengths between the indole and the carbamate group and with differently substituted aryl moieties at the carbamate oxygen were synthesized and tested for inhibition of the pharmacologically interesting serine hydrolases fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), butyrylcholinesterase (BuChE), and acetylcholinesterase (AChE). Furthermore, the chemical stability in an aqueous solution and the metabolic stability toward esterases in porcine liver homogenate and porcine blood plasma were determined. While most of the synthesized derivatives were potent inhibitors of FAAH, a considerable inhibition of MAGL and BuChE was elicited only by compounds with a high carbamate reactivity, as evidenced by a significant hydrolysis of these compounds in an aqueous solution. However, the high inhibitory potency of some compounds toward MAGL and BuChE, especially that of the ortho-carboxyphenyl derivative 37, could not be explained by chemical reactivity alone. Several of the carbamates studied possessed varying degrees of stability toward esterases from liver and blood plasma. In some cases, marked inactivation by the pseudo-esterase activity of plasma albumin was observed. Mass spectrometric studies showed that such carbamates formed covalent bonds with albumin at several sites.

SUBMITTER: Rudolph S

PROVIDER: S-EPMC8158844 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase: New Targets for Future Antidepressants.

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Project description:Monoacylglycerol lipase (MAGL) is a 33 kDa member of the serine hydrolase superfamily that preferentially degrades 2-arachidonoylglycerol (2-AG) to arachidonic acid in the endocannabinoid system. Inhibition of MAGL is not only of interest for probing the cannabinoid pathway but also as a therapeutic and diagnostic target for neuroinflammation. Limited attempts have been made to image MAGL in vivo and a suitable PET ligand for this target has yet to be identified and is urgently sought to guide small molecule drug development in this pathway. Herein we synthesized and evaluated the physiochemical properties of an array of eleven sulfonamido-based carbamates and ureas with a series of terminal aryl moieties, linkers and leaving groups. The most potent compounds were a novel MAGL inhibitor, N-((1-(1H-1,2,4-triazole-1-carbonyl)piperidin-4-yl) methyl)-4-chlorobenzenesulfonamide (TZPU; IC50 = 35.9 nM), and the known inhibitor 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(((4-chlorophenyl)sulfonamido) methyl)piperidine-1-carboxylate (SAR127303; IC50 = 39.3 nM), which were also shown to be selective for MAGL over fatty acid amide hydrolase (FAAH), and cannabinoid receptors (CB1 & CB2). Both of these compounds were radiolabeled with carbon-11 via [(11)C]COCl2, followed by comprehensive ex vivo biodistribution and in vivo PET imaging studies in normal rats to determine their brain permeability, specificity, clearance and metabolism. Whereas TZPU did not show adequate specificity to warrant further evaluation, [(11)C]SAR127303 was advanced for preliminary PET neuroimaging studies in nonhuman primate. The tracer showed good brain permeability (ca. 1 SUV) and heterogeneous regional brain distribution which is consistent with the distribution of MAGL.

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| S-EPMC3544278 | biostudies-literature

Insight into the Inhibitory Mechanism of Aryl Formyl Piperidine Derivatives on Monoacylglycerol Lipase through Molecular Dynamics Simulations.

Project description:Monoacylglycerol lipase (MAGL) can regulate the endocannabinoid system and thus becomes a target of antidepressant drugs. In this paper, molecular docking and molecular dynamics simulations, combined with binding free energy calculation, were employed to investigate the inhibitory mechanism and binding modes of four aryl formyl piperidine derivative inhibitors with different 1-substituents to MAGL. The results showed that in the four systems, the main four regions where the enzyme bound to the inhibitor included around the head aromatic ring, the head carbonyl oxygen, the tail amide bond, and the tail benzene ring. The significant conformational changes in the more flexible lid domain of the enzyme were caused by 1-substituted group differences of inhibitors and resulted in different degrees of flipping in the tail of the inhibitor. The flipping led to a different direction of the tail amide bond and made a greater variation in its interaction with some of the charged residues in the enzyme, which further contributed to a different swing of the tail benzene ring. If the swing is large enough, it can weaken the binding strength of the head carbonyl oxygen to its nearby residues, and even the whole inhibitor with the enzyme so that the inhibition decreases.

| S-EPMC9655140 | biostudies-literature

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