Endogenous Cannabinoids: Structure and Metabolism

Abstract

D9 -Tetrahydrocannabinol (THC), the main psychoactive compound extracted from Cannabis sativa, is the most representative component of the mixture of therapeutic substances that are communally referred to as cannabinoids (1). It acts as an agonist at specific G-protein-coupled receptors, cannabinoid receptor subtypes CB 1 and CB 2 (2). The discovery of cannabinoid receptors has driven the investigation of the existence of their natural ligands and, soon after, endocannabinoids were identified. N-arachidonoyl-ethanolamine (AEA, anandamide) and 2-arachidonoyl glycerol (2-AG) are the two most studied endocannabinoids. They are biosynthesised 'on demand' by cleavage of their membrane lipid precursors N-arachidonoyl-phosphatidylethanolamine (N-ArPE) and sn-1-acyl-2-arachidonoylglycerols (DAGs) respectively, and then inactivated by intracellular hydrolysing enzymes. Cannabinoid receptors, endocannabinoids and enzymes that biosynthesise [N-acyl-phosphatidylethanolamine-selective phospholipase D (NAPE-PLD) and diacylglycerol lipase (DAGL)] and degrade [fatty acid amide hydrolase (FAAH) and the monoacylglycerol lipases (MAGL)] AEA and 2-AG, respectively, are key components in the endocannabinoid system (3). Despite a large number of excellent studies having contributed to the current understanding of the endocannabinoid regulation and function, further efforts are necessary to fully comprehend this signalling system. Here, a review on the current knowledge on structure and metabolism of the best studied endogenous cannabinoids is presented. In particular, this review concentrates on the mechanisms responsible for the biosynthesis and inactivation of the endocannabinoids, as well as on the several inhibitors of their metabolism identified to date. Endocannabinoids and related N-acyl-ethanolaminesEndocannabinoids are defined as endogenous compounds capable of binding to and functionally activating cannabinoid receptors. At least five endocannabinoids have been identified to date (Fig. 1). Anandamide, the amide between arachidonic acid and ethanolamine, was the first endogenous ligand to be reported at the end of 1992 (4) and additional polyunsaturated ethanolamines that bind to cannabinoid receptors, homolinolenylethanolamide and docosatetraenylethanolamide, have been isolated in the brain. Other endocannabinoids, all derived from arachidonic acid, were identified. The identification of 2-AG, the ester of arachidonic acid with glycerol, isolated from canine gut and brain has also been reported (5, 6). Subsequently, the first endocannabinoid characterised by ether bond, 2-arachidonyl glyceryl ether or noladin ether, was isolated from porcine brain (7) and N-arachidonoyldopamine (NADA), a selective CB 1 agonist and a potent agonist of vanilloid receptors, was discovered (8, 9). O-arachidonoylethanolamine, the ester derivative of ethanolamine with arachidonic acid, with the same molecular weight as anandamide but with opposite orientation of the polar ethanolamine moiety, was named virodhamine from the Sanskrit word virodha, ...

CB1Receptors Mediate the Analgesic Effects of Cannabinoids on Colorectal Distension-Induced Visceral Pain in Rodents

“…Two cannabinoid receptor subtypes (CB 1 and CB 2 ) and a putative third cannabinoid receptor (referred to as GPR 55 ) have been identified (Howlett et al, 2002;Brown, 2007;Ryberg et al, 2007). All three cannabinoid receptors are activated by endogenous lipid ligands known as endocannabinoids, with anandamide and 2-arachinodonyl glycerol being the most abundant endocannabinoids (for review, see Bisogno, 2008;. CB 1 receptors (CB 1 Rs) are mostly expressed in the nervous system at both central and peripheral sites, including the enteric nervous system (Matsuda et al, 1990(Matsuda et al, , 1992Ahluwalia et al, 2000;Coutts et al, 2002;Bridges et al, 2003;MacNaughton et al, 2004).…”

Potencial uso terapéutico de cannabis

“…Se han identificado 400 El ser humano presenta una serie de receptores de membrana multifuncionales que responden a moléculas que, sin ser cannabinoides, se comportan como tales, son los llamados endocannabinoides 4 . Los endocannabinoides son lípidos bioactivos que al interaccionar con estas proteínas de membrana, causan efectos biológicos similares a los cannabinoides pero fisiológicamente controlados.…”

“…El receptor CB1 es un polipéptidodo de 472 aminoácidos, siendo el más abundante y de mayor distribución en el organismo humano. Se concentra en el cerebro, médula espinal y regiones sensoriales periféricas, donde modula funciones cerebrales como aprendizaje, memoria, emociones, movimiento, ciclos circadianos y de regulación central, además de funciones endocrinas, metabólicas y de balance energético [4][5][6] .…”

New Therapeutics in Hypertension

“…Anandamide (Naraquidonoiletanolamina, AEA) and 2-arachidonoylglycerol (2-AG) are the two best known endocannabinoids. AEA may be a partial or full agonist of CB1 receptors with low action over CB2 and 2-AG an agonist both of CB1 and CB2 receptors (Bisogno., 2008, Howlett., 2002.…”

“…(Bisogno., 2008) Recently there are results that demonstrate its high hypotensive efficiency in hypertensive animals compared with the normotensive ones and evidence that the tonic activation of the ECS in various experimental models of hypertension could be a possible compensatory mechanism. (Batkai et al, 2004, Wheal et al,2007 This hipotensive tone could be attributed to a decrease in the mediated activity by the CB1 receptor in myocardial contractility rather than vascular resistance.…”