Metabolism of N‐Acylethanolamines: To Phase II and Back Again

Abstract

N‐acylethanolamines (NAEs) are a family of endogenous signalling molecules involved in various effects of the body including pain, inflammation, appetite and sleep. NAEs are mainly degraded by fatty acid amide hydrolase (FAAH) and N‐acylethanolamine acid amidase (NAAA). FAAH inhibitors have shown promising results in preclinical studies of pain, inflammation and anxiety, mediating effects mainly via increased cannabinoid receptor activity. However, FAAH inhibitors have failed in clinical pain trials, and in a recent phase I trial, an irreversible compound caused one death and sustained impairments in healthy volunteers. The latter is most likely due to off‐target effects of that compound, rather than an FAAH‐mediated effect, and design of dual‐action FAAH‐NAAA, ‐TRPV1 or ‐cyclooxygenase‐2 inhibitory compounds may solve the pain efficacy issue. NAAA inhibitors are still in preclinical testing and show a promising anti‐inflammatory profile mainly due to increased palmitoylethanolamide and oleoylethanolamide levels.

Key Concepts

  • N‐acylethanolamines as a family of lipids with diverse biological activities involving different receptor pathways.
  • Fatty acid amide hydrolase and N‐acylethanolamine acid amidase as the main enzymes responsible for hydrolysis of N‐acylethanolamines in mammals.
  • A pharmacological strategy for treatment of anxiety, inflammation and/or pain by potentiation of N‐acylethanolamine signalling through inhibition of metabolic enzymes.
  • The predictive validity of animal tests for pain.
  • The importance of ‘off‐target’ actions of a drug on its safety.
  • The concept of dual action inhibitors as opposed to two drugs.

Keywords: N‐acylethanolamines; fatty acid amide hydrolase; degradation; N‐acylethanolamine acid amide hydrolase; cyclooxygenase‐2; TRPV1; dual target; inhibitor

Figure 1. Structure and plasma concentrations in healthy humans of the most common NAEs (N‐acylethanolamines). Blood samples were collected from healthy volunteers, lipids were extracted and analysed by ultra performance liquid chromatography coupled to tandem mass spectrometry. Abbreviations: PEA, palmitoylethanolamide; SEA, stearoylethanolamide; OEA, oleoylethanolamide; LEA, linoleoyl ethanolamide; AEA, anandamide. The NAEs are followed by (N:n), which indicates the number of carbon atoms and double bonds, respectively, in the side chain. Thus, AEA has 20 carbon atoms and four double bonds in the arachidonoyl side chain. Data are adapted from Hellström et al. 2016.
Figure 2. Structures of irreversible (top five compounds) and reversible (OL-135, MK-4409) FAAH (fatty acid amide hydrolase) inhibitors. Structures were collected using the MolGrabber function built into the ChemDoodle programme v 8.1.0 for the Macintosh (iChemLabs, LLC, Somerset, NJ, USA). BIA10‐2474 is an irreversible inhibitor of FAAH, but has been separated from the others in view of its catastrophic clinical trial.
Figure 3. Structures of systemically active NAAA (N‐acylethanolamine acid amide hydrolase) inhibitors. Note that while selectivity versus FAAH has been established, the selectivity of the compounds vis‐a‐vis other off‐targets is uncertain.
Figure 4. Derivation of dual‐action COX‐FAAH inhibitors from flurbiprofen.
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Karlsson, Jessica, and Fowler, Christopher J(Nov 2017) Metabolism of N‐Acylethanolamines: To Phase II and Back Again. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027664]