Synthesis of Phenoxyacyl-Ethanolamides and Their Effects on Fatty Acid Amide Hydrolase Activity

Faure, Lionel; Nagarajan, Subbiah; Hwang, Hyeondo; Montgomery, Christa; Khan, Bibi Rafeiza; John, George; Koulen, Peter; Blancaflor, Elison B.; Chapman, Kent D.

doi:10.1074/jbc.m113.533315

Cited by 18 publications

(25 citation statements)

References 47 publications

(68 reference statements)

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“…Indeed, allosteric sites are structurally much less conserved than catalytic sites, thus supporting the development of drugs -positive or negative heterotropic modulators -with much greater selectivity. In this context two phenoxyacyl-ethanolamides, 3-n-pentadecylphenolethanolamide and cardanolethanolamide, have been described as FAAH activators 42 , and it can be speculated that these non-hydrolysable analogues of N-acylethanolamines may stimulate hydrolysis of AEA and congeners by acting as positive allosteric modulators of FAAH.…”

Section: Discussionmentioning

confidence: 99%

The endocannabinoid hydrolase FAAH is an allosteric enzyme

Dainese

Oddi

Simonetti

et al. 2020

Sci Rep

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Fatty acid amide hydrolase (FAAH) is a membrane-bound homodimeric enzyme that in vivo controls content and biological activity of N-arachidonoylethanolamine (AEA) and other relevant bioactive lipids termed endocannabinoids. Parallel orientation of FAAH monomers likely allows both subunits to simultaneously recruit and cleave substrates. Here, we show full inhibition of human and rat FAAH by means of enzyme inhibitors used at a homodimer:inhibitor stoichiometric ratio of 1:1, implying that occupation of only one of the two active sites of FAAH is enough to fully block catalysis. Single W445Y substitution in rat FAAH displayed the same activity as the wild-type, but failed to show full inhibition at the homodimer:inhibitor 1:1 ratio. Instead, F432A mutant exhibited reduced specific activity but was fully inhibited at the homodimer:inhibitor 1:1 ratio. Kinetic analysis of AEA hydrolysis by rat FAAH and its F432A mutant demonstrated a Hill coefficient of ~1.6, that instead was ~1.0 in the W445Y mutant. Of note, also human FAAH catalysed an allosteric hydrolysis of AEA, showing a Hill coefficient of ~1.9. Taken together, this study demonstrates an unprecedented allosterism of FAAH, and represents a case of communication between two enzyme subunits seemingly controlled by a single amino acid (W445) at the dimer interface. In the light of extensive attempts and subsequent failures over the last decade to develop effective drugs for human therapy, these findings pave the way to the rationale design of new molecules that, by acting as positive or negative heterotropic effectors of FAAH, may control more efficiently its activity. Endocannabinoids form a relevant class of lipids that are widespread in tissues, where they exert diverse biological actions 1. Endocannabinoids have been demonstrated to reduce pain and inflammation, modulate energetic homeostasis and appetite, and have anticancer, anxiolytic, and neuroprotective effects through type-1 and/or type-2 cannabinoid receptors (CB 1 and CB 2), as well as via stimulation of transient receptor potential vanilloid channels, peroxisome proliferator-activated receptors, and additional targets 2-4. Their degradation is due to the activity of several metabolic enzymes, among which FAAH has a prominent role also in vivo 5. In addition, biotransformation of endocannabinoids is catalysed by lipoxygenases (LOXs) or cyclooxygenase-2 (COX-2) 6-8. FAAH is a membrane-bound homodimer that is able to hydrolyse AEA and, to a lesser extent, 2-arachidonoylglycerol (2-AG), N-oleoylethanolamine 9,10 , N-palmitoylethanolamine 11 , and N-oleoyltaurine 5,12,13. The biological activity of AEA, 2-AG and related compounds within the central nervous system 2,3 and at the periphery has been recently reviewed 6. The 3D structures of a truncated form of rat FAAH lacking the N-terminal region 14 (hereafter referred to as rFAAH), and of its humanized form containing residues of the human active site 15 , have been resolved at high resolution, and some details of the catalytic mechanism of the enzyme ha...

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Section: Discussionmentioning

confidence: 99%

The endocannabinoid hydrolase FAAH is an allosteric enzyme

Dainese

Oddi

Simonetti

et al. 2020

Sci Rep

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“…[26][27][28][29][30] In this line, John and co-workers reported the synthesis of phenoxyacylethanolamides from this CNSL and studied their amidohydrolase activity of fatty acid amide hydrolase (FAAH). 31 In this paper, we report a facile synthesis of amphiphilic N-acyl amides by the judicious combination of various amino alcohols such as dopamine, propanol amine, and tris, and the phenolic esters derived from cardanol and explored their molecular selfassembly in a wide variety of solvents and vegetable oils. We have also demonstrated the potential application of one of the amphiphilic N-acyl amides as a dual channel stimuli-responsive delivery system for the natural hydrophobic drug, curcumin.…”

Section: Introductionmentioning

confidence: 99%

Hybrid hydrogels derived from renewable resources as a smart stimuli responsive soft material for drug delivery applications

et al. 2022

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“…[53][54][55] Our recent research on molecular self-assembly using cardanol-based amphiphiles clearly demonstrate its significance. [23,[56][57][58][59][60][61][62] In this report, we have generated a set of three amphiphiles by a judicious combination of δ-gluconolactone and cardanol derivatives, which upon self-assembly via noncovalent interactions such as van der Waals forces, hydrogen bonding and π-π interactions at different intensities to furnish supramolecular gels. It is worth mentioning that supramolecular self-assembly is considered as one of the most powerful strategies to develop functional materials [63][64][65][66] bearing nano-architecture with tortuousness using the conventional top-down approach.…”

Section: Introductionmentioning

confidence: 99%

Supramolecular gels of gluconamides derived from renewable resources: Antibacterial and anti‐biofilm applications

et al. 2020

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Carbohydrates are versatile materials widely used for several applications including food, pharmaceuticals, cosmetics, and drug delivery systems due to their inherent properties such as non-toxicity, biodegradability, and bio-compatibility. Specifically, the urge on carbohydrate research is due to its significance in the biological system, for example, a glycoprotein found in the extracellular matrix, involved in signaling pathways, cell-cell interaction and cell-matrix interaction. Because of the increase in demand of glycolipids for biological applications, in this report, a set of three structurally related gluconamide-based amphiphiles were synthesized from renewable resources, δ-gluconolactone and cashew nut shell liquid. The molecular structure of the synthesized glycolipids was characterized by NMR and mass spectral techniques. Molecular self-assembly of gluconamide-based amphiphiles was investigated relative to the molecular structure and nature of the solvent used. Interestingly, the nature of the hydrophobic tail present in the glycolipids influences the self-assembly pattern, which results in a hydrogel, organogel and highly insoluble nanorods. Gelation studies clearly revealed that the involvement of different magnitude of non-covalent interactions such as hydrogen bonding, π-π stacking and van der Waals interaction. Morphology of self-assembled architecture was investigated by optical microscopy, FESEM and FETEM analysis. The mechanism involved in the molecular self-assembly has been deduced by small angle XRD analysis. Thermo reversibility and the thixotropic nature of the derived gels were identified by rheological measurements. Further, antimicrobial and biofilm inhibitory activity of gluconamide-based amphiphiles were studied against various pathogenic bacterial strains Staphylococcus aureus, Listeria monocytogenes, Salmonella This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Synthesis of Phenoxyacyl-Ethanolamides and Their Effects on Fatty Acid Amide Hydrolase Activity

Cited by 18 publications

References 47 publications

The endocannabinoid hydrolase FAAH is an allosteric enzyme

The endocannabinoid hydrolase FAAH is an allosteric enzyme

Hybrid hydrogels derived from renewable resources as a smart stimuli responsive soft material for drug delivery applications

Supramolecular gels of gluconamides derived from renewable resources: Antibacterial and anti‐biofilm applications

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