The classical definition of the endocannabinoid system (ECS), at the turn of the century, was that of a complex pleiotropic system composed by: (1) the two cannabinoid receptors (CB1 and CB2); (2) their endogenous ligands, the ‘endocannabinoids’ (EC) and (3) the five enzymes believed at that time to be uniquely responsible for EC biosynthesis and degradation. However, studies carried out during the last 10 years have revealed the potential existence of a high degree of redundancy for both the molecular targets and metabolic routes, and corresponding enzymes, of the ECs. Therefore, these new discoveries suggested that the time had come to expand our view of the ECS. In fact, other bioactive long chain fatty acid amides were identified, and their biosynthesis, inactivation and function investigated. Since this plethora of novel mediators has something more than a few chemical features in common with ECs, the name of ‘endocannabinoidome’ (eCBome) was proposed.

Key Concepts

  • The endocannabinoid system is an ever‐expanding pleiotropic signalling system with key role in several physiopathological conditions.
  • Studies carried out during the last 10 years have revealed the potential existence of a high degree of redundancy for both the molecular targets and metabolic routes, and corresponding enzymes, of the endocannabinoids.
  • Several N‐acyl‐ethanolamines (NAEs), monoacylglycerols, N‐acyl amino acids, N‐acyldopamines/taurines/serotonines were suggested to be part of this system.
  • These endocannabinoid‐like molecules may activate other molecular targets independently from cannabinoid receptors.
  • All these recent findings together with the discovery of new endocannabinoid‐like molecules have led us to expand the classical view of the eCB system and to look at it as the ‘endocannabinoidome’.

Keywords: endocannabinoids; cannabinoid receptors; enzymes; N‐acylamino acids; N‐acyldopamines; N‐acylserotonins; COX‐2 derivatives; fatty acid esters of hydroxyl fatty acids

Figure 1. The evolution of the endocannabinoid system from the classical description (a) to the new definition as theendocannabinoidome(b). ABH4/6/12, αβ‐hydrolase 4/6/12; CB1/2, cannabinoid receptor 1/2; COX2, cyclooxygenase 2; DAG, diacylglycerol; EMT, ‘endocannabinoid membrane transporter’; FAAH, fatty acid amide hydrolase; GDE1, glycerophosphodiester phosphodiesterase 1; GPR55, G‐protein‐coupled receptor 55; MAGL, monoacylglycerol lipase; NAPE‐PLD, N‐acylphosphatidylethanolamine‐selective phosphodiesterase; NATs, N‐acyltransferases; PA, phosphatidic acid; PLCβ, phospholipase Cβ; PLD, phospholipase D; PTPN22, protein tyrosine phosphatase, nonreceptor type 22; TRPV1, transient receptor potential, vanilloid subtype 1 receptor; GABAA, type‐A γ‐aminobutyric acid receptors; adenosine A3, adenosine A3 receptor; PPARγ, peroxisome proliferator‐activated receptor gamma; 15‐LOX, lipoxygenase‐15; PMs, prostaglandin‐ethanolamides/prostamides; PG‐GEs, prostaglandin‐glyceryl esters.
Figure 2. Chemical structures of different N‐acyl amino acids.
Figure 3. Chemical structures of different N‐acyldopamines.
Figure 4. Chemical structures of different N‐acylserotonins.
Figure 5. Chemical structures of different COX‐2 derivatives (a) and fatty acid esters of hydroxy fatty acids (b).


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Further Reading

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Tan B, Bradshaw HB, Rimmerman N, et al. (2006) Targeted lipidomics: discovery of new fatty acyl amides. The AAPS Journal 8 (3): E461–E465.

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Arturo, Iannotti Fabio, and Fabiana, Piscitelli(Nov 2018) Endocannabinoidome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0028301]