title: Advances in the discovery of N-acylethanolamine acid amidase inhibitors.
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.
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, I-16163 Genova, Italy. Electronic address: tiziano.bandiera@iit.it.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Bandiera
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, I-16163 Genova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ponzano
authors.affiliation: Drug Discovery and Development, Istituto Italiano di Tecnologia, Via Morego 30, I-16163 Genova, Italy; Departments of Anatomy and Neurobiology, Pharmacology and Biological Chemistry, University of California, Irvine 92697-4625, USA. Electronic address: piomelli@uci.edu.
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000700:Analgesics / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D007249:Inflammation / Q000188:drug therapy; D010146:Pain / Q000188:drug therapy
chemical_list: D000700:Analgesics; D004791:Enzyme Inhibitors; D000581:Amidohydrolases; C523108:NAAA protein, human
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)