Elsevier

Biochemical Pharmacology

Volume 62, Issue 5, 1 September 2001, Pages 517-526
Biochemical Pharmacology

Commentary
Fatty acid amide hydrolase: biochemistry, pharmacology, and therapeutic possibilities for an enzyme hydrolyzing anandamide, 2-arachidonoylglycerol, palmitoylethanolamide, and oleamide1

https://doi.org/10.1016/S0006-2952(01)00712-2Get rights and content

Abstract

Fatty acid amide hydrolase (FAAH) is responsible for the hydrolysis of a number of important endogenous fatty acid amides, including the endogenous cannabimimetic agent anandamide (AEA), the sleep-inducing compound oleamide, and the putative anti-inflammatory agent palmitoylethanolamide (PEA). In recent years, there have been great advances in our understanding of the biochemical and pharmacological properties of the enzyme. In this commentary, the structure and biochemical properties of FAAH and the development of potent and selective FAAH inhibitors are reviewed, together with a brief discussion on the therapeutic possibilities for such compounds in the treatment of inflammatory pain and ischaemic states.

Introduction

AEA, PEA, and oleamide belong to a class of biologically active endogenous fatty acid amides that have been the subject of increasing interest in recent years [for recent reviews, see Refs. [1], [2], [3], [4]. AEA is found in the brain, and shares many of the behavioral properties of cannabinoids such as Δ9-tetrahydrocannabinol, producing antinociception, hypothermia, hypomotility, and catalepsy [5]. AEA interacts with cannabinoid CB1 and CB2 receptors [see Ref. [6]] and vanilloid receptors [7]. In contrast, PEA does not interact with CB1 or CB2 receptors [8], but has been shown to prevent mast cell activation and to reduce inflammatory pain in vivo[9], [10], [11]. Both AEA and PEA are found in the skin [10], and it has been suggested that PEA acts as an autocoid capable of locally modulating mast cell activation in response to neurogenic inflammatory stimuli such as substance P [12]. Oleamide has been shown to induce sleep in experimental animals [13], possibly as a result of its effects upon GABAA receptors and voltage-gated Na+ channels [14].

In 1993, Deutsch and Chin [15] reported in this journal an amidase activity capable of the hydrolysis of AEA (reaction pathway, see Fig. 1). This enzymic activity, which they termed “anandamide amidase,” was sensitive to inhibition by the serine protease inhibitor PMSF, and was found in several tissues including the liver and brain [15]. In vivo, AEA administered i.v. to mice is transformed rapidly to arachidonic acid, so that most of the AEA reaching the brain has been metabolized by 15 min [16]. Initially, it was not clear whether the enzyme was related to the enzymic activity previously described by Natarajan et al.[17] that was capable of metabolizing PEA and other N-acylethanolamines. However, once the enzyme was cloned by Cravatt et al.[18], it was clear that a single enzyme was responsible for the metabolism of a wide variety of fatty acid amides. This enzyme is now generally termed FAAH.

The demonstration of an AEA-metabolizing activity, while of general scientific interest, was not of pharmacological importance until it was demonstrated that functional inhibition of the enzyme led to a significant potentiation of the actions of AEA, i.e. that the enzyme represented an important metabolic pathway in vivo. It is possible, for example, that other metabolic pathways for AEA (such as the oxidative pathways mediated by cyclooxygenase-2 and lipoxygenases; for a review, see Ref. [19]) are of greater importance. However, in 1997, Compton and Martin [20] reported that pretreatment of mice with PMSF, at doses that did not produce behavioral effects per se, potentiated 5- to 10-fold three out of the four behavioural actions of AEA investigated in the “tetrad” of tests used to identify cannabimimetic agents (see Fig. 2). This was mirrored by an increased brain level of AEA following its i.v. administration. Thus, the concentration of AEA in the brain following a dose of 10 mg/kg, i.v., was 0.13 ± 0.02 and 1.94 ± 0.67 μg/g for control and PMSF-pretreated animals, respectively [21]. PMSF also potentiated the effects of AEA upon electrically evoked contractions of a myenteric plexus preparation from guinea-pig small intestine [22]. In contrast, PMSF had considerably less effect upon the response in this preparation to R-methAEA, which is a poor substrate for FAAH [22]. Compton and Martin [20] concluded from their study that “these findings with PMSF underscore the importance of metabolism in the actions of anandamide” and thus indicate that FAAH inhibition may be a useful pharmacological strategy in potentiating the actions of this and other fatty acid amides. In this commentary, the authors will discuss the structure and biochemical properties of FAAH before describing recent advances in the synthesis of potent and selective FAAH inhibitors. Finally, therapeutic possibilities for FAAH inhibitors will be discussed briefly.

Section snippets

Cellular and subcellular localization of FAAH

FAAH is distributed widely throughout the body, and is found in brain, liver, testes, uterus, kidney, ocular tissues, spleen, and possibly lung, but not in skeletal muscle or heart [15], [18], [23], [24], [25], [26], [27]. Within the brain, FAAH expression varies from region to region, with the highest activities being found in the globus pallidus and hippocampus, and the lowest in the medulla [23], [28], [29]. The sensitivity of FAAH to different inhibitors is similar in different brain

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    Abbreviations: AEA, anandamide, arachidonyl ethanolamide; PEA, palmitoylethanolamide, N-(2-hydroxyethyl) hexadecamide; FAAH, fatty acid amide hydrolase; CB, cannabinoid; PMSF, phenylmethylsulfonyl fluoride; MAFP, methyl arachidonyl fluorophosphonate; methAEA, arachidonyl-1′-hydroxy-2′-propylamide; and NSAIDs, nonsteroidal anti-inflammatory drugs.

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