Fatty Acid Amide Hydrolase (FAAH), Acetylcholinesterase (AChE), and Butyrylcholinesterase (BuChE): Networked Targets for the Development of Carbamates as Potential Anti-Alzheimer’s Disease Agents

Montanari, Serena; Scalvini, Laura; Bartolini, Manuela; Belluti, Federica; Gobbi, Silvia; Andrisano, Vincenza; Ligresti, Alessia; Marzo, Vincenzo Di; Rivara, Silvia; Mor, Marco; Bisi, Alessandra; Rampa, Angela

doi:10.1021/acs.jmedchem.6b00609

Cited by 71 publications

(61 citation statements)

References 43 publications

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“…As the mutual constitute in Fr 5 and Fr 6 , N-benzylhexadecanamide (A 54 ) was selected to validate this mechanism as pure compound, which also displayed high AChE (IC 50 = 14.23 μg.mL −1 ) and BuChE (IC 50 = 17.54 μg.mL −1 ) inhibitory activities. What’s more, A 54 were reported as dual AChE/BuChE inhibitors without remarkable side effects535455. In conclusion, Fr 5 and macamides produced the healing efficacy by increasing the acetylcholine and butyrylcholine level in brain.…”

Section: Resultsmentioning

confidence: 99%

Chemical profiling analysis of Maca using UHPLC-ESI-Orbitrap MS coupled with UHPLC-ESI-QqQ MS and the neuroprotective study on its active ingredients

Zhou

Li²,

Brantner

et al. 2017

Sci Rep

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Lepidium meyenii (Maca), originated from Peru, has been cultivated widely in China as a popular health care food. However, the chemical and effective studies of Maca were less in-depth, which restricted its application seriously. To ensure the quality of Maca, a feasible and accurate strategy was established. One hundred and sixty compounds including 30 reference standards were identified in 6 fractions of methanol extract of Maca by UHPLC-ESI-Orbitrap MS. Among them, 15 representative active compounds were simultaneously determined in 17 samples by UHPLC-ESI-QqQ MS. The results suggested that Maca from Yunnan province was the potential substitute for the one from Peru. Meanwhile, the neuroprotective effects of Maca were investigated. Three fractions and two pure compounds showed strong activities in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced zebrafish model. Among them, 80% methanol elution fraction (Fr5) showed significant neuroprotective activity, followed by 100% part (Fr6). The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was a possible mechanism of its neuroprotective effect.

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Section: Resultsmentioning

confidence: 99%

Chemical profiling analysis of Maca using UHPLC-ESI-Orbitrap MS coupled with UHPLC-ESI-QqQ MS and the neuroprotective study on its active ingredients

Zhou

Li²,

Brantner

et al. 2017

Sci Rep

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“…FAAH and MAGL activities were detected in cells as previously described . In particular, AEA hydrolysis was measured by incubating samples with the 10 000× g membrane fraction of rat brain (70 μg per sample) and synthetic N ‐arachidonoyl‐[ 14 C]ethanolamine (110mCi mmol −1 , ARC, St. Louis, MO, USA) properly diluted with AEA (Tocris Bioscience, Avonmouth, Bristol, UK) in Tris⋅HCl 50 m m , at pH 9.00–10.00 at 37 °C for 30 min.…”

Section: Methodsmentioning

confidence: 99%

“…FAAH and MAGL activities were detected in cells as previously described. [44][45] In particular,AEA hydrolysis was measured by incubating samples with the 10 000 g membrane fraction of rat brain (70 mgp er sample) and synthetic N-arachidonoyl-[ 14 C]ethanolamine (110mCi mmol À1 ,A RC, St. Louis, MO, USA) properly diluted with AEA (Tocris Bioscience, Avonmouth, Bristol, UK) in Tris·HCl 50 mm, at pH 9.00-10.00 at 37 8Cf or 30 min. After incubation, the amount of [ 14 C]ethanolamine produced was measured by scintillation counting of the aqueous phase after extraction of the incubation mixture with two volumes of CHCl 3 /MeOH 1:1(v/v).…”

Section: Enzymatic Assaysmentioning

confidence: 99%

Development of Potent Inhibitors of Fatty Acid Amide Hydrolase Useful for the Treatment of Neuropathic Pain

et al. 2018

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The unique role of fatty acid amide hydrolase (FAAH) in terminating endocannabinoid (EC) signaling supports its relevance as a therapeutic target. Inhibition of EC metabolizing enzymes elicits indirect agonism of cannabinoid receptors (CBRs) and therapeutic efficacy devoid of psychotropic effects. Based on our previous ligands, and aiming at the discovery of new selective FAAH inhibitors, we developed a series of 12 new compounds characterized by functionalized tricyclic scaffolds. All the developed compounds display negligible activity on monoacylglycerol lipase (MAGL) and CBRs. The most potent FAAH inhibitors of the newly developed series, 6-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-6-phenylhexylcarbamate (5 h) and 4-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-(6-phenylhexyl)carbamate (5 i) (nanomolar FAAH inhibitors, the latter of which also shows micromolar affinity at the CB R), were selected for further studies. Results of cell-based studies on a neuroblastoma cell line (IMR32) demonstrated 5 h, 5 i, and our reference compound 3 ([3-(3-carbamoylpyrrol-1-yl)phenyl] N-(5-phenylpentyl)carbamate) to lack any cytotoxic effect, while all three showed the ability to decrease oxidative stress by reducing the expression of the redox-sensitive transcription factor NF-κB. Encouraged by these data, these compounds were studied in vivo and were dosed orally in a mouse model of neuropathic pain. At 10 mg kg all the compounds were able to relieve the hypersensitivity induced by oxaliplatin.

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“…Moreover, the screening of a diverse library of triazolothiadiazole and triazolothiadiazine scaffolds for bioactivities and cytotoxicity had also suggested some dual inhibitors of AChE and butyrylcholinesterase (BChE) . Finally, carbamates were developed as multitargeted agents modulating the bioactivity of the fatty acid amide hydrolase (FAAH) as well as both AChE and BChE . The goal was, through the inhibition of FAAH, to prevent or reduce the inflammatory process associated with Aβ deposition.…”

Section: Multitarget Approaches Involving Secretasementioning

confidence: 99%

“…292 Finally, carbamates were developed as multitargeted agents modulating the bioactivity of the fatty acid amide hydrolase (FAAH) as well as both AChE and BChE. 293 The goal was, through the inhibition of FAAH, to prevent or reduce the inflammatory process associated with Aβ deposition. Undoubtedly, there are still numerous targets to investigate and even more multitarget drugs to develop.…”

mentioning

confidence: 99%

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

Schaduangrat

Prachayasittikul

Choomwattana

et al. 2019

Medicinal Research Reviews

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The continual increase of the aging population worldwide renders Alzheimer's disease (AD) a global prime concern. Several attempts have been focused on understanding the intricate complexity of the disease's development along with the on‐ andgoing search for novel therapeutic strategies. Incapability of existing AD drugs to effectively modulate the pathogenesis or to delay the progression of the disease leads to a shift in the paradigm of AD drug discovery. Efforts aimed at identifying AD drugs have mostly focused on the development of disease‐modifying agents in which effects are believed to be long lasting. Of particular note, the secretase enzymes, a group of proteases responsible for the metabolism of the β‐amyloid precursor protein (βAPP) and β‐amyloid (Aβ) peptides production, have been underlined for their promising therapeutic potential. This review article attempts to comprehensively cover aspects related to the identification and use of drugs targeting the secretase enzymes. Particularly, the roles of secretases in the pathogenesis of AD and their therapeutic modulation are provided herein. Moreover, an overview of the drug development process and the contribution of computational (in silico) approaches for facilitating successful drug discovery are also highlighted along with examples of relevant computational works. Promising chemical scaffolds, inhibitors, and modulators against each class of secretases are also summarized herein. Additionally, multitarget secretase modulators are also taken into consideration in light of the current growing interest in the polypharmacology of complex diseases. Finally, challenging issues and future outlook relevant to the discovery of drugs targeting secretases are also discussed.

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Fatty Acid Amide Hydrolase (FAAH), Acetylcholinesterase (AChE), and Butyrylcholinesterase (BuChE): Networked Targets for the Development of Carbamates as Potential Anti-Alzheimer’s Disease Agents

Cited by 71 publications

References 43 publications

Chemical profiling analysis of Maca using UHPLC-ESI-Orbitrap MS coupled with UHPLC-ESI-QqQ MS and the neuroprotective study on its active ingredients

Chemical profiling analysis of Maca using UHPLC-ESI-Orbitrap MS coupled with UHPLC-ESI-QqQ MS and the neuroprotective study on its active ingredients

Development of Potent Inhibitors of Fatty Acid Amide Hydrolase Useful for the Treatment of Neuropathic Pain

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

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