oleylamide and palmidrol

During the last eight years a number of bioactive lipid mediators, the amides or esters of long chain fatty acids, have been discovered or re-discovered. These are: anandamide (N-arachidonoyl-ethanolamine, AEA) and 2-arachidonoylglycerol (2-AG), two endogenous agonists of cannabinoid receptors; oleamide (cis-9-octadecenoamide), a putative endogenous sleep-inducing factor; N-palmitoylethanol amine (PEA), a compound with promising anti-inflammatory and immune-modulatory activity. These compounds are all substrates for the same hydrolytic enzyme, fatty acid amide hydrolase (FAAH), whose molecular characterization was obtained in 1996. The molecular and enzymatic properties, tissue distribution, substrate recognition properties, physiological regulation and biological role of FAAH are discussed in this article, with special emphasis on the possible pharmacological manipulation of the activity of this enzyme with therapeutic purpose.

Topics: Amides; Amidohydrolases; Animals; Arachidonic Acids; Endocannabinoids; Enzyme Inhibitors; Ethanolamines; Glycerides; Humans; Mice; Molecular Sequence Data; Oleic Acids; Palmitic Acids; Polyunsaturated Alkamides; Rats; Sequence Homology, Amino Acid; Structure-Activity Relationship; Substrate Specificity; Swine

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.

Topics: Amides; Amidohydrolases; Animals; Arachidonic Acids; Endocannabinoids; Enzyme Inhibitors; Ethanolamines; Glycerides; Humans; Oleic Acids; Palmitic Acids; Polyunsaturated Alkamides

Palmitoylethanolamide (PEA) and oleamide are two fatty acid amides which 1) share some cannabimimetic actions with delta9-tetrahydrocannabinol, anandamide and 2-arachidonoylglycerol, and 2) may interact with proteins involved in the biosynthesis, action and inactivation of endocannabinoids. Due to its pharmacological actions and its accumulation in damaged cells, PEA may have a physio-pathological role as an analgesic, anti-oxidant and anti-inflammatory mediator. However, its mechanism of action is puzzling. In fact, PEA does not bind to CB1 and CB2 receptors transfected into host cells, but might be a ligand for a putative CBn receptor present in the RBL-2H3 cell line. On the other hand, the analgesic effect of PEA is reversed by SR144528, a CB2 antagonist. PEA may act as an entourage compound for endocannabinoids, i.e. it may enhance their action for example by inhibiting their inactivation. Oleamide is a sleep inducing lipid whose mechanism of action is far from being understood. Although it does not bind with high affinity to CB1 or CB2 receptors, it exhibits some cannabimimetic actions which could be explained at least in part by entourage effects. It is likely that oleamide and anandamide have common as well as distinct pathways of action. The 5-HT2A receptor appears to be a target for oleamide but the possibility of the existence of specific receptors for this compound is open. The biosynthesis and tissue distribution of oleamide remain to be assessed in order to both substantiate its role as a sleep-inducing factor and investigate its participation in other physiopathological situations.

Topics: Amides; Animals; Cannabinoid Receptor Modulators; Cannabinoids; Endocannabinoids; Ethanolamines; Humans; Hypnotics and Sedatives; Oleic Acids; Palmitic Acids; Receptors, Cannabinoid; Receptors, Drug