Abstract
N-Acylethanolamines (NAEs) are involved in numerous biological activities in plant and animal systems. The metabolism of these lipids by fatty acid amide hydrolase (FAAH) is a key regulatory point in NAE signaling activity. Several active site-directed inhibitors of FAAH have been identified, but few compounds have been described that enhance FAAH activity. Here we synthesized two sets of phenoxyacyl-ethanolamides from natural products, 3-n-pentadecylphenolethanolamide and cardanolethanolamide, with structural similarity to NAEs and characterized their effects on the hydrolytic activity of FAAH. Both compounds increased the apparent Vmax of recombinant FAAH proteins from both plant (Arabidopsis) and mammalian (Rattus) sources. These NAE-like compounds appeared to act by reducing the negative feedback regulation of FAAH activity by free ethanolamine. Both compounds added to seedlings relieved, in part, the negative growth effects of exogenous NAE12:0. Cardanolethanolamide reduced neuronal viability and exacerbated oxidative stress-mediated cell death in primary cultured neurons at nanomolar concentrations. This was reversed by FAAH inhibitors or exogenous NAE substrate. Collectively, our data suggest that these phenoxyacyl-ethanolamides act to enhance the activity of FAAH and may stimulate the turnover of NAEs in vivo. Hence, these compounds might be useful pharmacological tools for manipulating FAAH-mediated regulation of NAE signaling in plants or animals.
Highlights
Fatty acid amide hydrolase (FAAH) belongs to the family of amidase signature proteins and is involved in N-acylethanolamine (NAE) metabolism
Phenoxyacyl-Ethanolamide Synthesis—We developed a simple method that proceeds by refluxing the mixture of phenolic lipids 3-PDP (Fig. 1, 1) or cardanol [2] and methylbromoacetate in the presence of K2CO3 as a base and 2-butanone as a solvent to generate the desired PDP-methylester [3] or cardanolmethylester [4], [35, 36]
Despite the structural similarity between the phenoxyacylethanolamide compounds synthesized for these studies (Fig. 1) and the naturally occurring NAE lipids that are present in essentially all multicellular eukaryotes, neither of the FAAH proteins were able, in our conditions, to utilize these compounds efficiently as substrates for hydrolysis (Fig. 3)
Summary
Fatty acid amide hydrolase (FAAH) belongs to the family of amidase signature proteins and is involved in N-acylethanolamine (NAE) metabolism. We synthesized two sets of phenoxyacyl-ethanolamides from natural products, 3-n-pentadecylphenolethanolamide and cardanolethanolamide, with structural similarity to NAEs and characterized their effects on the hydrolytic activity of FAAH Both compounds increased the apparent Vmax of recombinant FAAH proteins from both plant (Arabidopsis) and mammalian (Rattus) sources. Our data suggest that these phenoxyacyl-ethanolamides act to enhance the activity of FAAH and may stimulate the turnover of NAEs in vivo These compounds might be useful pharmacological tools for manipulating FAAH-mediated regulation of NAE signaling in plants or animals. We synthesized a new set of phenoxyacyl-ethanolamides from this cashew nut shell liquid renewable resource with structural similarity to NAEs to investigate their effects on FAAH activity and to explore the potential utility of natural mixtures in cardanol ethanolamide compared with the pure, saturated analog pentadecylphenoxy ethanolamide.
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