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Review
. 2014 Aug:86:11-7.
doi: 10.1016/j.phrs.2014.04.011. Epub 2014 May 4.

Advances in the discovery of N-acylethanolamine acid amidase inhibitors

Tiziano Bandiera  1 , Stefano Ponzano  2 , Daniele Piomelli  3
Affiliations
Review

Advances in the discovery of N-acylethanolamine acid amidase inhibitors

Tiziano Bandiera et al. Pharmacol Res. 2014 Aug.

Abstract

N-Acylethanolamine acid amidase (NAAA) is a cysteine amidase that hydrolyzes saturated or monounsaturated fatty acid ethanolamides, such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). PEA has been shown to exert analgesic and anti-inflammatory effects by engaging peroxisome proliferator-activated receptor-α. Like other fatty acid ethanolamides, PEA is not stored in cells, but produced on demand from cell membrane precursors, and its actions are terminated by intracellular hydrolysis by either fatty acid amide hydrolase or NAAA. Endogenous levels of PEA and OEA have been shown to decrease during inflammation. Modulation of the tissue levels of PEA by inhibition of enzymes responsible for the breakdown of this lipid mediator may represent therefore a new therapeutic strategy for the treatment of pain and inflammation. While a large number of inhibitors of fatty acid amide hydrolase have been discovered, few compounds have been reported to inhibit NAAA activity. Here, we describe the most representative NAAA inhibitors and briefly highlight their pharmacological profile. A recent study has shown that a NAAA inhibitor attenuated heat hyperalgesia and mechanical allodynia caused by local inflammation or nerve damage in animal models of pain and inflammation. This finding encourages further exploration of the pharmacology of NAAA inhibitors.

Keywords: (4-Phenylphenyl)methyl N-[(2S,3R)-2-methyl-4-oxooxetan-3-yl]carbamate (PubChem CID: 73291988); 3-Phenyl-1-pyrrolidin-1-ylpropan-1-one (PubChem CID: 1533088); 5-Phenylpentyl N-[(2S,3R)-2-methyl-4-oxooxetan-3-yl]carbamate (PubChem CID: 57523549); Fatty acid ethanolamides; Inflammation; N-Acylethanolamine acid amidase; N-Pentadecylbenzamide (PubChem CID: 44398681); N-Pentadecylcyclohexancarboxamide (PubChem CID: 44398718); N-[(3S)-2-Oxooxetan-3-yl]-3-phenylpropanamide (PubChem CID: 25227533); N-[(3S)-2-Oxooxetan-3-yl]-4-phenylbenzamide (PubChem CID: 46899632); NAAA inhibitors; Oleoylethanolamide (PubChem CID: 5283454); Pain; Palmitoylethanolamide; Palmitoylethanolamide (PubChem CID: 4671); Pentadecylamine (PubChem CID: 17386).

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Conflict of interest statement

Conflict of interest: The authors declare the following competing financial interests: T. Bandiera, S. Ponzano and D. Piomelli are inventors in patent applications protecting β-lactones reported in the present review.

Figures

Fig. 1
Fig. 1
Chemical structures of anandamide, oleoylethanolamide, and palmitoylethanolamide.
Fig. 2
Fig. 2
(A) Chemical structures of amides, retro-amides, esters, and retro-esters of palmitic acid. (B) Chemical structures of selected NAAA inhibitors.
Fig. 3
Fig. 3
(A) General structures of serine-derived β-lactones. (B) Chemical structures of selected serine-derived β-lactone NAAA inhibitors.
Fig. 4
Fig. 4
(A) General structure of threonine-derived β-lactones. (B) Chemical structures of selected threonine-derived β-lactones.
See this image and copyright information in PMC

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